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Drugs acting by inhibition of the angiogenic action of VEGF (vascular endothelial growth factor) have become major instruments in the treatment of cancer. The downside of their favorable effects in cancer treatment is their frequent cardiovascular side effects. The most consistent finding thus far on the cardiovascular side effects of VEGF inhibitors is the high incidence of hypertension. In this short review, we discuss the evidence that hypertension occurring during VEGF inhibitor treatment is caused by microvascular rarefaction. After a review of the role of VEGF in microvascular growth and differentiation, we present evidence from studies in experimental models of hypertension as well as clinical studies on the microvascular network changes during and after VEGF inhibitor treatment.

Aims: Hypertension and hypercholesterolemia are independent risk factors for atherosclerotic cardiovascular disease (ASCVD) by acting directly on the endothelium and activating the renin-angiotensin aldosterone system (RAAS) and mevalonate pathways. This review examines how the severity and duration of these risk factors may influence the cardiovascular risk through a reciprocal interplay leading to oxidative stress and pro-inflammatory response., Data Synthesis: The review highlights the clinical evidence supporting the benefits of statins and angiotensin-converting enzyme (ACE) inhibitors for hypertension, lipid disorders and ASCVD management, both individually and combined, at all stages of the cardiovascular continuum., Conclusion: Drug strategies incorporating an ACE-inhibitor and a statin, and in particular perindopril and atorvastatin, have consistently demonstrated reductions in the rate of ASCVD events in patients with hypertension and lipid disorders, cementing their position as first-line therapies for the management of atherosclerosis complications., Competing Interests: Declaration of competing interest B. I. Levy received honoraria and funding from Bayer, Roche and Servier. C. Borghi received fees as a speaker bureau from Servier, Novartis, Novo-Nordisk, Menarini Corporate, Alfasigma, Berlin-Chemie, Sanofi, and received honoraria as member of Advisory Board from Servier, Novartis, Alnylam, Alfasigma, Merck-Serono S.p.a., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Since December 2019, the coronavirus 2019 (COVID-19) pandemic has rapidly spread and overwhelmed healthcare systems worldwide, urging physicians to understand how to manage this novel infection. Early in the pandemic, more severe forms of COVID-19 have been observed in patients with cardiovascular comorbidities, who are often treated with renin-angiotensin aldosterone system (RAAS)-blockers, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), but whether these are indeed independent risk factors is unknown. The cellular receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the membrane-bound angiotensin converting enzyme 2 (ACE2), as for SARS-CoV(-1). Experimental data suggest that expression of ACE2 may be increased by RAAS-blockers, raising concerns that these drugs may facilitate viral cell entry. On the other hand, ACE2 is a key counter-regulator of the RAAS, by degrading angiotensin II into angiotensin (1-7), and may thereby mediate beneficial effects in COVID-19. These considerations have raised concerns about the management of these drugs, and early comments shed vivid controversy among physicians. This review will describe the homeostatic balance between ACE-angiotensin II and ACE2-angiotensin (1-7) and summarize the pathophysiological rationale underlying the debated role of the RAAS and its modulators in the context of the pandemic. In addition, we will review available evidence investigating the impact of RAAS blockers on the course and prognosis of COVID-19 and discuss why retrospective observational studies should be interpreted with caution. These considerations highlight the importance of solid evidence-based data in order to guide physicians in the management of RAAS-interfering drugs in the general population as well as in patients with more or less severe forms of SARS-CoV-2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gressens, Leftheriotis, Dussaule, Flamant, Levy and Vidal-Petiot.)

Purpose:  To assess the prognostic value of the wall shear stress (WSS) measured in the feeding native arteries upstream from facial superficial arteriovenous malformations (sAVMs). Reliable prognostic criteria are needed to distinguish progressive from stable sAVMs and thus support the indication for an aggressive or a conservative management to avoid severe facial disfigurement., Materials and Methods:  We prospectively included 25 patients with untreated facial sAVMs, 15 patients with surgically resected sAVMs and 15 controls. All had undergone Doppler ultrasound examination (DUS) with measurements of inner diameters, blood flow velocities, computation of blood flow and WSS of the feeding arteries. Based on the absence or presence of progression in clinical and imaging examinations 6 months after, we discriminated untreated patients as stable or progressive., Results:  WSS in the ipsilateral external carotid artery was higher in progressive compared to stable sAVMs (15.8 ± 3.3dynes/cm² vs. 9.6 ± 2.0dynes/cm², mean±SD, p < 0.0001) with a cut-off of 11.5dynes/cm² (sensitivity: 92 %, specificity: 92 %, AUC: 0.955, [95 %CI: 0.789-0.998], p = 0.0001). WSS in the ipsilateral facial artery was also higher in progressive compared to stable sAVMs (50.7 ± 14.5dynes/cm² vs. 25.2 ± 7.1dynes/cm², p < 0.0001) with a cut-off of 34.0dynes/cm² (sensitivity: 100 %, specificity: 92 %, AUC: 0.974, [95 %CI: 0.819-1.000], p = 0.0001). The hemodynamic data of operated patients were not different from those of the control group., Conclusion:  WSS measured in the feeding arteries of an sAVM may be a simple reliable criterion to distinguish stable from progressive sAVMs. This value should be considered to guide the therapeutic strategy as well as the long-term follow-up of patients with facial sAVMs., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Obstructive disease of the epicardial coronary arteries is the main cause of angina. However, a number of patients with anginal symptoms have normal coronaries or non-obstructive coronary artery disease (CAD) despite electrocardiographic evidence of ischaemia during stress testing. In addition to limited microvascular vasodilator capacity, the coronary microcirculation of these patients is particularly sensitive to vasoconstrictor stimuli, in a condition known as microvascular angina. This review briefly summarizes the determinants and control of coronary blood flow (CBF) and myocardial perfusion. It subsequently analyses the mechanisms responsible for transient myocardial ischaemia: obstructive CAD, coronary spasm and coronary microvascular dysfunction in the absence of epicardial coronary lesions, and variable combinations of structural anomalies, impaired endothelium-dependent and/or -independent vasodilation, and enhanced perception of pain. Lastly, we exemplify mechanism of angina during tachycardia. Distal to a coronary stenosis, coronary dilator reserve is already recruited and can be nearly exhausted at rest distal to a severe stenosis. Increased heart rate reduces the duration of diastole and thus CBF when metabolic vasodilation is no longer able to increase CBF. The increase in myocardial oxygen consumption and resulting metabolic vasodilation in adjacent myocardium without stenotic coronary arteries further acts to divert blood flow away from the post-stenotic coronary vascular bed through collaterals., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease, is associated with cognitive decline in middle-aged adults, but the mechanisms underlying this association are not clear. We hypothesized that NAFLD would unveil the appearance of brain hypoperfusion in association with altered plasma and brain lipid metabolism. To test our hypothesis, amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were fed a standard diet or a high-fat, cholesterol and cholate diet, inducing NAFLD without obesity and hyperglycemia. The diet-induced NAFLD disturbed monounsaturated and polyunsaturated fatty acid (MUFAs, PUFAs) metabolism in the plasma, liver, and brain, and particularly reduced n-3 PUFAs levels. These alterations in lipid homeostasis were associated in the brain with an increased expression of Tnfα , Cox2 , p21 , and Nox2 , reminiscent of brain inflammation, senescence, and oxidative stress. In addition, compared to wild-type (WT) mice, while brain perfusion was similar in APP/PS1 mice fed with a chow diet, NAFLD in APP/PS1 mice reveals cerebral hypoperfusion and furthered cognitive decline. NAFLD reduced plasma β 40 - and β 42 -amyloid levels and altered hepatic but not brain expression of genes involved in β-amyloid peptide production and clearance. Altogether, our results suggest that in a mouse model of Alzheimer disease (AD) diet-induced NAFLD contributes to the development and progression of brain abnormalities through unbalanced brain MUFAs and PUFAs metabolism and cerebral hypoperfusion, irrespective of brain amyloid pathology that may ultimately contribute to the pathogenesis of AD.

Context: Controversial data exist on cardiovascular damages in patients with congenital adrenal hyperplasia (CAH)., Objective: To assess blood pressure and early cardiovascular damages on a large cohort of adult CAH patients and control individuals., Design: Case-control study., Setting: Referral Center for Rare Disease, Pitié Salpêtrière Hospital, Paris, France., Patients or Other Participants: Fifty-eight women and 26 men with CAH diagnosed in childhood and 85 controls matched-paired for sex, age and smoking status were prospectively included., Intervention: Measurement of large arteries and microcirculatory anatomical and functional indices as well as hormonal status and cardiovascular risk factors evaluation., Main Outcome Measure: The primary objective was to compare carotid intima-media thickness (cIMT) in CAH patients and controls. The secondary objectives were to compare blood pressure (BP), radial augmentation index (rAI), central BP, carotid-femoral pulse wave velocity (PWV), skin microcirculation indices and inflammation parameters in CAH patients and controls., Results: Although PWV and cIMT were identical in patients and controls, higher rAI (64.6 ± 1.7 vs. 59.9 ± 1.6%, P = 0.02) and higher central SBP (101.8 ± 1.5 vs. 95.1 ± 1.5 mmHg, P < 0.001) were observed in CAH patients. Regarding microcirculatory indices, there was a higher functional resting capacity and a lower anatomical capillary density in CAH patients. In multivariate analysis, we found an independant association between CAH and central SBP elevation., Conclusion: We found an early rise in central SBP in CAH patients whereas sublinical arterial damages markers were normal. Our study suggest that vascular damages and increased cardiovascular risk could be mainly BP-driven.

Clinical trials of cell therapy in stroke favor autologous cell transplantation. To date, feasibility studies have used bone marrow-derived mononuclear cells, but harvesting bone marrow cells is invasive thus complicating bedside treatment. We investigated the therapeutic potential of peripheral blood-derived mononuclear cells (PB-MNC) harvested from diabetic patients and stimulated by ephrin-B2 (PB-MNC+) (500,000 cells), injected intravenously 18-24 hours after induced cerebral ischemia in mice. Infarct volume, neurological deficit, neurogenesis, angiogenesis, and inflammation were investigated as were the potential mechanisms of PB-MNC+ cells in poststroke neurorepair. At D3, infarct volume was reduced by 60% and 49% compared to unstimulated PB-MNC and PBS-treated mice, respectively. Compared to PBS, injection of PB-MNC+ increased cell proliferation in the peri-infarct area and the subventricular zone, decreased microglia/macrophage cell density, and upregulated TGF- β expression. At D14, microvessel density was decreased and functional recovery was enhanced compared to PBS-treated mice, whereas plasma levels of BDNF, a major regulator of neuroplasticity, were increased in mice treated with PB-MNC+ compared to the other two groups. Cell transcriptional analysis showed that ephrin-B2 induced phenotype switching of PB-MNC by upregulating genes controlling cell proliferation, inflammation, and angiogenesis, as confirmed by adhesion and Matrigel assays. Conclusions . This feasibility study suggests that PB-MNC+ transplantation poststroke could be a promising approach but warrants further investigation. If confirmed, this rapid, noninvasive bedside cell therapy strategy could be applied to stroke patients at the acute phase.

Background: Left ventricular (LV) torsion plays a key role in cardiac efficiency. In hypertension, aortic stiffening augments cardiac afterload. However, little is known about the links between LV regional contraction and aortic stiffness. We, therefore, investigated these relationships and their contribution to LV diastolic function., Methods and Results: The study included normotensive and hypertensive individuals with normal LV ejection. Apical, basal, and global LV rotation rate and LV global longitudinal strain were measured (2-dimensional speckle tracking echocardiography). Aortic stiffness was calculated from carotid-femoral pulse wave velocity, and LV relaxation was calculated from early diastolic mitral annulus motion. The ratio of basal or apical untwist/twist rates was calculated to assess relationships between aortic stiffness and LV torsion parameters. LV twist and untwist rates were greater in hypertensive than normotensive individuals because of increased basal twist ( P <0.001) and untwist ( P <0.001) rates. LV relaxation was reduced (early diastolic mitral annulus motion=7.4±1.9 versus 10.4±2.3 cm/s; P <0.001). In the whole population, basal untwist rate increased with aortic stiffening ( R =0.43; P <0.001) and LV relaxation ( R =0.41; P =0.001). The ratio of basal untwist/twist rate was positively correlated with carotid-femoral pulse wave velocity, and in the hypertensive group, was greater than in the control group and positively correlated to carotid-femoral pulse wave velocity( P <0.001). Results were independent of age, treatment, mean blood pressure, and indexed LV mass., Conclusions: In hypertensive individuals, greater basal LV torsion was associated with increased aortic stiffness and improved diastolic function. These changes may compensate for the deleterious effects of aortic stiffening on LV relaxation., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Mottling around the knee, reflecting a reduced skin blood flow, is predictive of mortality in patients with septic shock. However, the causative pathophysiology of mottling remains unknown. We hypothesized that the cutaneous hypoperfusion observed in the mottled area is related to regional endothelial dysfunction., Methods: This was a prospective, observational study in a medical ICU in a tertiary teaching hospital. Consecutive adult patients with sepsis admitted to ICU were included. After resuscitation, endothelium-dependent vasodilation in the skin circulation was measured before and after iontophoresis of acetylcholine (Ach) in the forearm and the knee area. We analyzed the patterns of induced vasodilatation according to the presence or absence of mottling and vital status at 14 days., Results: We evaluated 37 septic patients, including 11 without and 26 with septic shock. Overall 14-day mortality was 22%. Ten patients had mottling around the knee (10/37, 27%). In the knee area, the increased skin blood flow following iontophoresis of Ach was lower in patients with mottled skin as compared to patients without mottled skin (area under curve (AUC) 3280 (2643-6440) vs. 7980 (4233-19,707), both P < 0.05). In the forearm area, the increased skin blood flow following iontophoresis of Ach was similar in patients with and without mottled skin. Among patients with septic shock, the increased skin blood flow following iontophoresis of Ach in the knee area was significantly lower in non-survivors as compared to survivors at 14 days (AUC 3256 (2600-4426) vs. 7704 (4539-15,011), P < 0.01). In patients with septic shock, the increased skin blood flow in the forearm area following iontophoresis of Ach was similar in survivors and non-survivors at 14 days., Conclusion: Mottling is associated with regional endothelial dysfunction in patients with septic shock. Endothelial dysfunction in the knee skin area was more pronounced in non-survivors than in survivors.

Heart rate plays a major role in myocardial ischemia. A high heart rate increases myocardial performance and oxygen demand and reduces diastolic time. Ivabradine reduces heart rate by inhibiting the If current of sinoatrial-node cells. In contrast to beta-blockers, ivabradine has no negative inotropic and lusitropic effect for a comparable heart rate reduction. Consequently, diastolic duration is increased with ivabradine compared to beta-blockers. This has potential consequences on coronary blood flow since compression of the vasculature by the surrounding myocardium during systole impedes flow and coronary blood flow is mainly diastolic. Moreover, ivabradine does not unmask alpha-adrenergic vasoconstriction and, unlike beta-blockers, maintains coronary dilation during exercise. In comparison with beta-blockers, ivabradine increases coronary flow reserve and collateral perfusion promoting the development of coronary collaterals. Ivabradine attenuates myocardial ischemia and its consequences even in the absence of heart rate reduction, possibly through reduced formation of reactive oxygen species. In conclusion, ivabradine differs from other anti-anginal agents by improving coronary blood flow and by additional pleiotropic effects. These properties make ivabradine an effective anti-anginal and anti-ischemic agent for the treatment of patients with coronary artery disease., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: In patients with chronic kidney disease (CKD), severe anemia is associated with increased cardiovascular risk. Although elevating hemoglobin (Hb) and hematocrit (Hct) levels with erythropoiesis-stimulating agents (ESA) improves patients' quality of life, normalization of Hb does not reduce cardiovascular risk and the reason remains unclear., Main Methods: We measured the effect of acute isovolumic changes in Hct from 37±5 to 50±2% (mean±SD) on arterial blood pressure (BP), cardiac output (CO), and carotid and renal blood flow (BF), (1) in control rats and (2) after acute blockade of the nitric oxide (NO) pathway by l-NAME., Key Findings: 1) In control conditions, BP, CO and carotid and renal BF remained stable for Hct values between 38±2 and 46±1%; 2) for higher Hct values, BP rose together with increasing blood viscosity whereas CO and renal BF decreased; 3) during acute NO blockade, CO, and carotid and renal BF were significantly reduced and remained low whereas BP increased with Hct thus increasing blood viscosity. Our results suggest (1) the ceiling level of endothelium-mediated vasodilation for high values of blood viscosity under control conditions, and (2) the need for efficient endothelial function for vasomotor adaptation of hemodynamic resistances to blood viscosity., Significance: (1) Clinical benefits of ESA in CKD patients with severe endothelial dysfunction are primarily due to increased oxygen transport and supply and, (2) normalization of Hct values in these patients may prove deleterious because of significant increases in BP and reductions in BF associated with high blood viscosity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: Treatment of hypertensive patients with β-blockers reduces heart rate and decreases central blood pressure less than other antihypertensive drugs, implying that reducing heart rate without altering brachial blood pressure could increase central blood pressure, explaining the increased cardiovascular risk reported with β-blocker. We describe a randomized, double-blind study to explore whether heart rate reduction with the If inhibitor ivabradine had an impact on central blood pressure. We included 12 normotensive patients with stable coronary artery disease, heart rate ≥70 bpm (sinus rhythm), and stable background β-blocker therapy. Patients received ivabradine 7.5 mg BID or matched placebo for two 3-week periods with a crossover design and evaluation by aplanation tonometry. Treatment with ivabradine was associated with a significant reduction in resting heart rate after 3 weeks versus no change with placebo (-15.8±7.7 versus +0.3±5.8 bpm; P=0.0010). There was no relevant between-group difference in change in central aortic systolic blood pressure (-4.0±9.6 versus +2.4±12.0 mm Hg; P=0.13) or augmentation index (-0.8±10.0% versus +0.3±7.6%; P=0.87). Treatment with ivabradine was associated with a modest increase in left ventricular ejection time (+18.5±17.8 versus +2.8±19.3 ms; P=0.074) and a prolongation of diastolic perfusion time (+215.6±105.3 versus -3.0±55.8 ms with placebo; P=0.0005). Consequently, ivabradine induced a pronounced increase in Buckberg index, an index of myocardial viability (+39.3±27.6% versus -2.5±13.5% with placebo; P=0.0015). In conclusion, heart rate reduction with ivabradine does not increase central aortic blood pressure and is associated with a marked prolongation of diastolic perfusion time and an improvement in myocardial perfusion index., Clinical Trial Registration: URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-004779-35., (© 2015 American Heart Association, Inc.)

Background: It has been hypothesized that arterial stiffness leads to generalized microvascular dysfunction and that individuals with type 2 diabetes mellitus (T2DM) are particularly prone to the detrimental effects of arterial stiffness. However, evidence for an association between stiffness and markers of generalized microvascular dysfunction is lacking. We therefore investigated the association between arterial stiffness and skin microvascular function in individuals without and with T2DM., Methods: Cross-sectional data were used of The Supplementation en Vitamines et Mineraux Antioxydants 2 (SUVIMAX2) Study (n = 284/62.2 years/48.6% women/0% T2DM (by design)) and The Maastricht Study (n = 737/59.7 years/45.2% women/28.8% T2DM (by design)). Arterial stiffness was determined by carotid-femoral pulse wave velocity (cfPWV). Skin capillaroscopy was used to determine capillary density at baseline, and during reactive hyperemia and venous congestion. Laser Doppler flowmetry was used to assess acetylcholine- and local heating-induced vasoreactivity, and skin flowmotion., Results: In The SUVIMAX2 Study, cfPWV (per +1 SD) was not associated with baseline capillary density (regression coefficient: -0.48 (95% confidence interval: 2.37; 1.41)) or capillary recruitment during venous congestion (0.54% (-0.74; 1.81%)). In addition, cfPWV was not associated with acetylcholine (-0.02% (-0.14; 0.10%)) or local heating-induced vasoreactivity (0.03% (-0.07; 0.12%)). In The Maastricht Study, in individuals without T2DM, cfPWV was not associated with baseline capillary density (-1.20 (-3.17; 0.77)), and capillary recruitment during reactive hyperemia (1.22% (-0.41; 2.84%)) or venous congestion (1.50% (-0.25; 3.25%)). In addition, cfPWV was not associated with flowmotion (-0.01 (-0.07; 0.06)). Results were adjusted for age and sex. Additional adjustments for confounders did not materially change these results. Results were qualitatively similar in individuals with T2DM., Conclusions: Arterial stiffness is not associated with skin microvascular function, irrespective of the presence of T2DM., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Endothelial progenitor cell (EPC) transplantation has beneficial effects for therapeutic neovascularization. We therefore assessed the effect of a therapeutic strategy based on EPC administration in the healing of radiation-induced damage. To improve cell therapy for clinical use, we used pretreatment with ephrin B2-Fc (Eph-B2-Fc) and/or coadministration with smooth muscle progenitor cells. At day 3, EPCs promoted dermal wound healing in both nonirradiated and irradiated mice by 1.2- and 1.15-fold, respectively, compared with animals injected with phosphate-buffered saline. In addition, EPCs also improved skin-blood perfusion and capillary density in both irradiated and nonirradiated mice compared with PBS-injected animals. We also demonstrated that activation with Eph-B2-Fc increased wound closure by 1.6-fold compared with unstimulated EPCs in nonirradiated mice. Interestingly, the beneficial effect of Eph-B2-Fc was abolished in irradiated animals. In addition, we found that Eph-B2-Fc stimulation did not improve EPC-induced vascular permeability or adhesiveness compared to unstimulated EPCs. We hypothesized that this effect was due to high oxidative stress during irradiation, leading to inhibition of EPCs' beneficial effect on vascular function. In this line, we demonstrated that, in irradiated conditions, N-acetyl-l-cysteine treatment restored the beneficial effect of EPC stimulation with Eph-B2-Fc in the wound healing process. In conclusion, stimulation by Eph-B2-Fc improved the beneficial effect of EPCs in physiological conditions and irradiated conditions only in association with antioxidant treatment. Additionally, cotherapy was beneficial in pathological conditions.

Background: Patho-physiological and pharmacological studies have consistently noticed that, with the exception of subjects with end-stage renal disease, total intravascular blood volume is not increased in patients with chronic hypertension., Methods: Because the mean circulatory pressure is enhanced in such subjects, it was postulated that the compliance of the cardiovascular system could be abnormally low in this particular population. This simple observation has influenced a great part of our experimental and clinical research directed toward subjects with hypertension and their relationship with the compliance of the vascular system., Results: These works started between 1970 and 1980 by methodological investigations and validations followed by analysis of clinical situations that showed that venous and mostly arterial stiffness were significantly increased in hypertensive patients independently of blood pressure level. During the same time, we assessed the role of endothelium on the large arterial wall mechanical properties in normotensive and hypertensive rats. Thereafter more specific directions have been developed, affecting large arteries structure and function and arterial wall remodeling, including their consequences on central and peripheral hemodynamics. In parallel, epidemiological studies identified the pulsatile hemodynamic parameters as major independent predictors of cardiovascular risks., Conclusions: The consequences of these alterations on clinical pharmacology and therapeutics in hypertension are analyzed in detail., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Determine the effect of repeated intravitreal injections of ranibizumab (0.5 mg; 0.05 ml) on retrobulbar blood flow velocities (BFVs) using ultrasound imaging quantification in twenty patients with exudative age-related macular degeneration treated for 6 months., Methods: Visual acuity (ETDRS), central macular thickness (OCT), peak-systolic, end-diastolic and mean-BFVs in central retinal (CRA), temporal posterior ciliary (TPCA) and ophthalmic (OA) arteries were measured before, 2 days, 3 weeks and 6 months after the first injection. Patients were examined monthly and received 1-5 additional injections depending on ophthalmologic examination results., Results: Six months after the first injection, a significant increase in visual acuity 50.9 ± 25.9 versus 44.4 ± 21.7 (p < 0.01) and decrease in mean central macular thickness 267 ± 74 versus 377 ± 115 μm (p < 0.001) were observed compared to baseline. Although mean-BFVs decreased by 16%±3% in CRA and 20%±5% in TPCA (p < 0.001) 2 days after the first injection, no significant change was seen thereafter. Mean-BFVs in OA decreased by 19%±5% at week 3 (p < 0.001). However, the smallest number of injections (two injections) was associated with the longest time interval between the last injection and month 6 (20 weeks) and with the best return to baseline levels for mean-BFVs in CRA, suggesting that ranibizumab had reversible effects on native retinal vascular supply after its discontinuation. Moreover, a significant correlation between the number of injections and percentage of changes in mean-BFVs in CRA was observed at month 6 (R = 0.74, p < 0.001) unlike TPCA or OA., Conclusion: Ranibizumab could impair the native choroidal and retinal vascular networks, but its effect seems reversible after its discontinuation., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type-specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs.

Disruption of cerebral blood flow after stroke induces cerebral tissue injury through multiple mechanisms that are not yet fully understood. Smooth muscle cells (SMCs) in blood vessel walls play a key role in cerebral blood flow control. Cerebral ischemia triggers these cells to switch to a phenotype that will be either detrimental or beneficial to brain repair. Moreover, SMC can be primarily affected genetically or by toxic metabolic molecules. After stroke, this pathological phenotype has an impact on the incidence, pattern, severity, and outcome of the cerebral ischemic disease. Although little research has been conducted on the pathological role and molecular mechanisms of SMC in cerebrovascular ischemic diseases, some therapeutic targets have already been identified and could be considered for further pharmacological development. We examine these different aspects in this review.

Hypertension is a multifactorial systemic chronic disorder through functional and structural macrovascular and microvascular alterations. Macrovascular alterations are featured by arterial stiffening, disturbed wave reflection and altered central to peripheral pulse pressure amplification. Microvascular alterations, including altered wall-to-lumen ratio of larger arterioles, vasomotor tone abnormalities and network rarefaction, lead to disturbed tissue perfusion and susceptibility to ischemia. Central arterial stiffness and microvascular alterations are common denominators of organ damages. Vascular alterations are intercorrelated, amplifying the haemodynamic load and causing further damage in the arterial network. A plausible precursor role of vascular alterations in incident hypertension provides new insights for preventive and therapeutic strategies targeting macro and microvasculature. Cumulative metabolic burden and oxidative stress lead to chronic endothelial injury, promoting structural and functional vascular alterations, especially in the microvascular network. Pathophysiology of hypertension may then be revisited, based on both macrovascular and microvascular alterations, with a precursor role of endothelial dysfunction for the latter.

Objective: Microvascular dysfunction is suggested to be a marker of common pathophysiological mechanisms in the development of insulin resistance, cardiovascular diseases, and type 2 diabetes mellitus. Given the established relationship of diet with the macrovascular disease, the aim of this study was to investigate for the first time the possible associations between dietary patterns and microcirculation., Approach and Results: Two hundred ninety-one healthy men and women selected from the Supplementation en Vitamines et Mineraux Antioxydants 2' cohort were assessed for anthropometric, nutritional, biochemical, and microcirculation parameters using finger skin capillaroscopy. Dietary intake was assessed cross-sectionally using a food frequency questionnaire, and principal component analysis was used to identify dietary patterns from 40 food groups. Six dietary patterns were identified. A dietary pattern characterized by increased consumption of vegetable oils, poultry, and fish and seafood was positively associated with both functional and anatomic capillary density after adjusting for confounders (β=0.13, P=0.05 and β=0.20, P=0.00, respectively). A second dietary pattern with increased consumption of sweets was inversely associated with functional and anatomic capillary density in all multivariate models (β=-0.14, P=0.03 and β=-0.17, P=0.01). There were no associations between any of the derived dietary patterns and capillary recruitment., Conclusions: In healthy subjects, a dietary pattern characterized by an increased consumption of vegetable oils, poultry, and fish and seafood and low consumption of sweets was associated with better microvascular function. Further prospective studies are needed to confirm the present association.

Background: Hepatic pedicle clamping is often required to reduce blood loss and transfusion during liver resection. However, the question remains whether use of hepatic pedicle clamping promotes tumor growth. Endothelial progenitor cells (EPCs) are mobilized from bone marrow in response to tissue ischemia, which allows neovascularization of ischemic tissue. It has been suggested that EPCs are involved in tumor progression. We hypothesized that hepatic ischemia reperfusion (I/R)-induced mobilization of EPCs could enhance growth of microscopic tumor, therefore promoting liver metastasis in a mouse model of colorectal cancer., Materials and Methods: We used mouse models of hepatic I/R and hind limb ischemia. For comparison, we studied mice that underwent limb ischemia as positive controls of EPC mobilization. At day 0, we divided 40 mice into four groups: hepatic I/R, hind limb ischemia, combined hepatic I/R and hind limb ischemia, and control (sham midline incision laparotomy). At day 2, we induced liver metastasis in all mice by injecting CT-26 cells into the spleen. Time-dependent circulating EPCs were determined by flow cytometry. We evaluated liver metastasis and microvascular density on day 21., Results: The number of circulating progenitor cells increased rapidly in the ischemic groups compared with the control group. Hepatic I/R significantly increased tumor outgrowth compared with the control group. Increased tumor growth was associated with enhanced CD31-positive microvascular density in liver tissue., Conclusions: Hepatic I/R leads to mobilization of bone marrow-derived EPCs and enhanced intra-hepatic angiogenesis, which is associated with increased tumor burden in an animal model of colorectal liver metastasis., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Active Crohn's disease affects intestine but may alter other locations as eyes vasculature. Previous studies provide evidence of elevated blood flow velocities (BFv) and volume (BFV) in superior mesenteric artery (SMA). We prospectively studied hemodynamics in feeding arteries of bowel and eyes before and 2 weeks after treatment induction with anti-TNFα., Methods: Fifteen patients (5 females, 10 males, 35.4 ± 9.0 years, mean ± SD) with active Crohn's disease for 7.5 ± 7.7 years were enrolled. Ultrasound imaging was performed before and 2 weeks after treatment in SMA and retrobulbar arteries: central retinal (CRA), temporal posterior ciliary (TPCA) and ophthalmic (OA) arteries. Serum markers of inflammation (CRP and fibrinogen), arterial blood pressures (ABP) and skin flow-mediated dilation (sFMD) were measured and patients were compared to 10 control age- and sex-matched subjects., Results: Before treatment, CRP and fibrinogen plasma concentrations, SMA BFV (339 ± 100 mL/min) were higher in patients than in controls by 8.5-fold (p<0.001), 1.4-fold (p<0.01) and 1.5-fold, respectively (p<0.01). BFv in CRA (3.5 ± 0.7 cm/s) and TPCA (4.4 ± 1.0 cm/s), sFMD (371 ± 469%) were significantly lower than in controls by 83%, 73% and 52% respectively (p<0.05). Two weeks after treatment, CRP and fibrinogen decreased, SMA BFV was normalized (230 ± 39L/min, p<0.01), BFv in CRA, TPCA and OA increased respectively to 4.0 ± 1.1 (p<0.05), 5.2 ± 1.4 (p<0.001), 8.9 ± 3 cm/s (p<0.05). ABP and sFMD remained unchanged., Conclusions: In active Crohn's disease, a first anti-TNFα administration rapidly normalized concomitantly plasma inflammatory markers and blood-flows in the mesenteric and retrobulbar arteries without affecting blood pressure and endothelial function., (Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Inflammation plays a key role in ischemic stroke pathophysiology: microglial/macrophage cells and type-1 helper cells (Th1) seem deleterious, while type-2 helper cells (Th2) and regulatory T cells (Treg) seem protective. CD4 Th0 differentiation is modulated by microglial cytokine secretion. Glatiramer Acetate (GA) is an immunomodulatory drug that has been approved for the treatment of human multiple sclerosis by means of a number of mechanisms: reduced microglial activation and pro-inflammatory cytokine production, Th0 differentiation shifting from Th2 to Th2 and Treg with anti-inflammatory cytokine production and increased neurogenesis. We induced permanent (pMCAo) or transient middle cerebral artery occlusion (tMCAo) and GA (2 mg) or vehicle was injected subcutaneously immediately after cerebral ischemia. Mice were sacrificed at D3 to measure neurological deficit, infarct volume, microglial cell density and qPCR of TNFα and IL-1β (pro-inflammatory microglial cytokines), IFNγ (Th2 cytokine), IL-4 (Th2 cytokine), TGFβ and IL-10 (Treg cytokines), and at D7 to evaluate neurological deficit, infarct volume and neurogenesis assessment. We showed that in GA-treated pMCAo mice, infarct volume, microglial cell density and cytokine secretion were not significantly modified at D3, while neurogenesis was enhanced at D7 without significant infarct volume reduction. In GA-treated tMCAo mice, microglial pro-inflammatory cytokines IL-1β and TNFα were significantly decreased without modification of microglial/macrophage cell density, cytokine secretion, neurological deficit or infarct volume at D3, or modification of neurological deficit, neurogenesis or infarct volume at D7. In conclusion, Glatiramer Acetate administered after cerebral ischemia does not reduce infarct volume or improve neurological deficit in mice despite a significant increase in neurogenesis in pMCAo and a microglial pro-inflammatory cytokine reduction in tMCAo., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Metabolic syndrome (MetS), an important component of insulin resistance and cardiovascular (CV) risk, is defined by 3 or more of the following characteristics: abdominal obesity, hyperglycemia, hypertension, hypertriglyceridemia, and hypo-high-density lipoprotein cholesterolemia. Based on the previously published age- and sex-mediated DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) cohort and parallel central hemodynamic measurements, our goal was to evaluate the effects of MetS on brachial central pulse pressure (PP), PP amplification, aortic stiffness, and wave reflections. These data were then compared with those of patients with essential hypertension but without MetS for the same mean arterial pressure. Increased aortic stiffness, a major mechanical factor predicting CV risk, has been well identified as playing a role in MetS. Its age progression is proportional to the number of risk factors involved in MetS and is responsible for increased systolic blood pressure and decreased diastolic blood pressure with increasing age, the principal hallmarks of hypertension in the elderly. Beyond brachial pressure measurements, central hemodynamic parameters involve increased aortic stiffness, reduced wave reflections, and increased PP amplification, a parameter commonly associated with increased heart rate. With the exception of arterial stiffness, all these findings are opposite in direction to those observed in essential hypertension, in which MetS is absent. A divergent behavior of wave reflections and PP amplification, but not of arterial stiffness, is observed when hypertension is studied alone or when compared with MetS for the same mean arterial pressure. This pulsatile hemodynamic abnormality contributes independently to increase age- and sex-mediated CV risk, justifying new research regarding Framingham scores and drug treatment., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We tested the effect of acetazolamide on blood mechanical properties and pulmonary vascular resistance (PVR) during chronic hypoxia. Six groups of rats were either treated or not treated with acetazolamide (curative: treated after 10 days of hypoxic exposure; preventive: treated before hypoxic exposure with 40 mg · kg(-1) · day(-1)) and either exposed or not exposed to 3 weeks of hypoxia (at altitude >5,500 m). They were then used to assess the role of acetazolamide on pulmonary artery pressure, cardiac output, blood volume, haematological and haemorheological parameters. Chronic hypoxia increased haematocrit, blood viscosity and PVR, and decreased cardiac output. Acetazolamide treatment in hypoxic rats decreased haematocrit (curative by -10% and preventive by -11%), PVR (curative by -36% and preventive by -49%) and right ventricular hypertrophy (preventive -20%), and increased cardiac output (curative by +60% and preventive by +115%). Blood viscosity was significantly decreased after curative acetazolamide treatment (-16%) and was correlated with PVR (r=0.87, p<0.05), suggesting that blood viscosity could influence pulmonary haemodynamics. The fall in pulmonary vascular hindrance (curative by -27% and preventive by -45%) after treatment suggests that acetazolamide could decrease pulmonary vessels remodelling under chronic hypoxia. The effect of acetazolamide is multifactorial by acting on erythropoiesis, pulmonary circulation, haemorheological properties and cardiac output, and could represent a pertinent treatment of chronic mountain sickness.

Pro-angiogenic cell-based therapies constitute an interesting and attractive approach to enhancing post-stroke neurogenesis and decreasing neurological deficit. However, most new stroke-induced neurons die during the first few weeks after ischemia, thus impairing total recovery. Although the neovascularization process involves different cell types and various growth factors, most cell therapy protocols are based on the biological effects of single-cell-type populations or on the administration of heterogeneous populations of progenitors, namely human cord blood-derived CD34(+) cells, with scarce vascular progenitor cells. Tight cooperation between endothelial cells and smooth muscle cells/pericytes is critical for the development of functional neovessels. We hypothesized that neuroblast survival in stroke brain depends on mature vascular network formation. In this study, we injected a combination of endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs), isolated from human umbilical cord blood, into a murine model of permanent focal ischemia induced by middle cerebral artery occlusion. The co-administration of SMPCs and EPCs induced enhanced angiogenesis and vascular remodeling in the peri-infarct and infarct areas, where vessels exhibited a more mature phenotype. This activation of vessel growth resulted in the maintenance of neurogenesis and neuroblast migration to the peri-ischemic cortex. Our data suggest that a mature vascular network is essential for neuroblast survival after cerebral ischemia, and that co-administration of EPCs and SMPCs may constitute a novel therapeutic strategy for improving the treatment of stroke., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)