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T cell-based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low- dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome., Introduction Tumor growth is driven by oncogenic signaling within a protumorigenic microenvironment. Cotargeting different tumor components has the potential to enhance anticancer treatments, including immunotherapies, but implementation of combination therapies [...]

Nine years ago, the compound kynurenine was reported to be responsible for the dilation of blood vessels during a potentially fatal inflammatory condition. New evidence has now identified the true culprit. A re-evaluation of a factor involved in vasodilation., Author(s): David A. Kass Author Affiliations: Fresh evidence overturns the identification of a factor involved in blood-vessel dilation In the life-threatening condition known as sepsis, the body responds to infection [...]

Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases., Introduction Formation of new blood vessels from preexisting vessels, i.e., angiogenesis, encompasses a series of morphogenic events that include sprouting at the vascular front, branching, lumen formation, anastomoses, and remodeling [...]

Increased activity in perivascular fibroblasts could precede motor-neuron degeneration and be a predictor of shorter survival in amyotrophic lateral sclerosis., Author(s): Collin J. Kreple [sup.1] , Kathleen M. Schoch [sup.1] , Timothy M. Miller [sup.1] Author Affiliations: (1) Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. [...]

Chronic total occlusions (CTOs) are commonly found in patients with coronary artery disease, and a system of collateral connections are found in almost all of these patients. These collateral vessels serve to prevent myocardial necrosis but are not sufficient to prevent myocardial ischemia during exercise. Unfortunately, the presence of well-developed collaterals has been used as argument against CTO revascularization. Many continue to falsely believe that these patients are 'protected' by collaterals and, therefore, CTO recanalization is not indicated. Our knowledge of the physiologic significance of coronary collaterals has increased significantly over the past several years. Studies utilizing coronary pressure and flow velocity have answered a number of basic physiologic questions. We therefore sought to review the evidence for coronary collateral flow and their clinical significance in patients with CTOs. Key words: coronary artery disease, chronic total occlusions, percutaneous coronary interventions, angioplasty. L'occlusion totale chronique (OTC) est frequemment trouvee chez les patients atteints d'une coronaropathie, et un systeme de connections collaterales est observe chez presque tous ces patients. Ces vaisseaux collateraux servent a prevenir la necrose du myocarde mais ils ne suffisent pas a prevenir l'ischemie myocardique durant l'exercice. Malheureusement, la presence de vaisseaux collateraux bien developpes a ete evoquee comme argument contre la revascularisation des OTC. Plusieurs personnes continuent de croire a tort que ces patients sont << proteges >> par les vaisseaux collateraux et consequemment, la recanalisation de l'OTC n'est pas indiquee. Notre comprehension de l'importance physiologique des vaisseaux coronaires collateraux s'est significativement accrue au cours des dernieres annees. Des etudes utilisant la pression coronarienne et la vitesse d'ecoulement ont repondu a plusieurs questions physiologiques de base. Les auteurs desiraient consequemment passer en revue les donnees portant sur le flux des vaisseaux collateraux coronariens et leur importance clinique chez les patients qui presentent des OTC. [Traduit par la Redaction] Mots-cles : coronaropathie, occlusions totales chroniques, interventions coronariennes percutanees, angioplastie., Introduction Chronic total occlusions (CTOs) are common and can be seen in 15%-35% of patients with coronary artery disease (Christofferson et al. 2005; Fefer et al. 2012; Jeroudi et al. [...]

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, autosomal-recessive disorder associated with several clinical features including obesity, hypertension, and cardiovascular abnormalities. BBS proteins play an important role in the function of cilia, a mechanosensory organelle in endothelial cells, but whether these proteins are directly involved in the regulation of vascular function is unclear. Here, we show that Bbs genes (1-12) are expressed in endothelial and smooth muscle cell lines and tissues enriched in endothelial (lung) and smooth muscle (stomach) cells as well as the aorta. Next, we used aortic rings to examine the vascular function of two BBS mouse models that recapitulate the human phenotype, namely [Bbs2.sup.-/-] (obese and normotensive) and [Bbs6.sup.-/-] (obese and hypertensive) mice. Interestingly, the endothelium-dependent relaxation (induced by ACh) was significantly enhanced in [Bbs2.sup.-/-] but not [Bbs6.sup.-/-] mice. In contrast, the endothelium-independent relaxation (induced by sodium nitroprusside) was unaltered in both BBS mouse models. In addition, the contractile responses to serotonin and endothelin-1 were attenuated in [Bbs2.sup.-/-] but not [Bbs6.sup.-/-] mice. Of note, the NO-producing enzymes (eNOS and iNOS) were upregulated in the aorta of [Bbs2.sup.-/-] but not [Bbs6.sup.-/-] mice. On the other hand, the expression level of membrane subunits of NADPH oxidase ([p22.sup.phox] and [p47.sup.phox]) in the aorta was decreased in [Bbs2.sup.-/-] mice but increased in [Bbs6.sup.-/-] mice. In conclusion, these data implicate Bbs genes in the regulation of vascular function and demonstrate that disrupting Bbs2 and Bbs6 genes affect differentially the vascular function. obesity; hypertension; vascular reactivity doi: 10.1152/ajpheart.00336.2010.

Capsaicin-sensitive extrinsic sensory nerves and submucosal vasodilator neurons provide important vasodilator input to submucosal arterioles, but relatively little is known about the signaling between these populations and the sympathetic vasoconstrictor innervation. This study examined whether release of sympathetic purines can modulate dilator nerves. In vitro submucosal preparations from guinea pig ileum were modified to leave the parent mesenteric artery intact so that perivascular sympathetic and extrinsic afferent nerves could be activated by a bipolar stimulating electrode placed on the parent artery, and submucosal vasodilator neurons were activated using focal electrodes placed on submucosal ganglia. The outside diameter of submucosal arterioles was monitored using videomicroscopy, and dilator responses were examined after preconstricting vessels 80-95% with prostaglandin [F.sub.2[alpha]] (400 nM). Mesenteric nerve stimulation evoked a frequency-dependent dilation, with suramin (100 [micro]M) present throughout to inhibit P2x receptor-mediated vasoconstrictions. In the presence of guanethidine (10 [micro]M) to inhibit sympathetic purine release, superfusion of ATP (200 nM-6 [micro]M) caused a concentration-dependent inhibition of nerve-evoked dilations. Vasodilations to substance P (10 nM) were not inhibited by ATP in the presence of guanethidine, implicating a presynaptic effect of ATP on neurotransmitter release. The inhibitory effect of ATP was blocked by the adenosine receptor antagonist 8-phenyltheophylline (8-PT; 10 [micro]M). In addition, 8-PT increased the amplitude of nerve-evoked dilations, suggesting a tonic inhibitory effect of adenosine receptors on vasodilator release. Dilations evoked by electrical stimulation of submucosal ganglia were also inhibited almost 50% by ATP (2 [micro]M) and its nonhydrolyzable analog, [alpha],[beta]-methylene-ATP (10 [micro]M). These data suggest that sympathetic varicosities release ATP or a related purine that can act at presynaptic adenosine receptors on extrinsic sensory and submucosal vasodilator neurons to inhibit neurotransmitter release. purinergic neurotransmission; vasodilation; extrinsic afferent neuron; substance P doi: 10.1152/ajpgi.00291.2009.

Numerous epidemiological studies have shown that cardiovascular dysfunction in adult life may be programmed by compromised growth in utero. Aging is a risk factor for vascular endothelial-dependent dysfunction. After birth, the impact of intrauterine growth restriction (IUGR) on normal aging mechanisms of vascular dysfunction is not known. We hypothesized that IUGR would cause changes in vascular function that would affect the mechanisms of endothelium-dependent vasodilation later in life in an age- or sex-dependent manner. To create an IUGR model, pregnant Sprague-Dawley rats were placed in a hypoxic (12% [O.sub.2]) or control (room air, 21% [O.sub.2]) environment from days 15 to 21 of the pregnancy, and both male and female offspring were investigated at 4 or 12 mo of age. Endothelial function was assessed in small mesenteric arteries using methacholine (MCh)-induced vasodilation in a wire myograph system. The involvement of nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF) was assessed using the inhibitors [N.sup.[omega]]-nitro-L-arginine methyl ester hydrochloride, meclofenamate, or a combination of apamin and TRAM-34 ([SK.sub.Ca] and [IK.sub.Ca] blockers), respectively. EDHF-induced vasodilation was further investigated by using inhibitors of P450 epoxygenases [N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide] and gap junctions (18[alpha]-glycyrrhetinic acid). NO-mediated vasodilation was significantly reduced in aged controls and both young and aged IUGR females. EDHF-mediated vasodilation was maintained in all groups; however, an additional involvement of gap junctions was found in females exposed to hypoxia in utero, which may represent a compensatory mechanism. A change in the mechanisms of vasodilation occurring at an earlier age in IUGR offspring may predispose them to adult cardiovascular diseases. IUGR; hypoxia; nitric oxide; EDHF; myoendothelial gap junctions doi: 10.1152/ajpregu.00641.2009.

Am J Physiol Regul Integr Comp Physiol 298: R51-R60, 2010. First published November 4, 2009; doi: 10.1152/ajpregu.00576.2009.--Hypoxic pulmonary vasoconstriction (HVC), an intrinsic and assumed ubiquitous response of mammalian pulmonary blood vessels, matches regional ventilation to perfusion via an unknown O2-sensing mechanism. Global pulmonary hypoxia experienced by individuals suffering from chronic obstructive pulmonary disease or numerous hypoventilation syndromes, including sleep apnea, often produces maladaptive pulmonary hypertension, but pulmonary hypertension is not observed in diving mammals, where profound hypoxia is routine. Here we examined the response of cow and sea lion pulmonary arteries (PA) to hypoxia and observed the expected HVC in the former and a unique hypoxic vasodilation in resistance vessels in the latter. We then used this disparate response to examine the [O.sub.2]-sensing mechanism. In both animals, exogenous [H.sub.2]S mimicked the vasoactive effects of hypoxia in isolated PA. [H.sub.2]S-synthesizing enzymes, cystathionine [beta]-synthase, cystathionine [gamma]-lyase, and 3-mercaptopyruvate sulfur transferase, were identified in lung tissue from both animals by one-dimensional Western blot analysis and immunohistochemistry. The relationship between [H.sub.2]S production/consumption and [O.sub.2] was examined in real time by use of amperometric [H.sub.2]S and [O.sub.2] sensors. H2S was produced by sea lion and cow lung homogenate in the absence of [O.sub.2], but it was rapidly consumed when [O.sub.2] was present. Furthermore, consumption of exogenous [H.sub.2]S by cow lung homogenate, PA smooth muscle cells, and heart mitochondria was [O.sub.2] dependent and exhibited maximal sensitivity at physiologically relevant [Po.sub.2] levels. These studies show that HVC is not an intrinsic property of PA and provide further evidence for [O.sub.2]-dependent [H.sub.2]S metabolism in [O.sub.2] sensing. hypoxic vasoconstriction; pinniped; pulmonary hypertension

Background: To decrease the morbidity associated with cut-downs during endovascular aneurysm repair, some authors have suggested the totally percutaneous endovascular repair (PEVAR). The goal of this report is to evaluate and describe our centre&apos;s experience with the total percutaneous endovascular aneurysm repair (PEVAR) for aortic abdominal aneurysm (AAA). Methods: We performed a retrospective analysis of 15 consecutive patients with AAA, including 1 with right common iliac artery aneurysm. Results: There were 12 men and 3 women with a mean age of 74 (standard deviation [SD] 2) years who underwent PEVAR with a Perclose ProGlide suture-mediated closure system between July 2007 and July 2008. All surgeries were elective. Forty percent of patients had a history of smoking, 73% were hypertensive, 33% were diabetic, 20% had chronic obstructive pulmonary disease and 40% had coronary artery disease. Fourteen patients had bilateral deployment for bifurcated devices (7 bifurcated Gore Excluder, 7 bifurcated Cook Zenith grafts), and 1 patient had unilateral deployment for a Cook Zenith device. The outer diameter of the sheaths used for puncture sites was on average 18.1-Fr (SD 0.6), with main bodies being 21.1-Fr (SD 0.3) and contralateral sides 15-Fr (SD 0.3). Procedural success was 93%, with 1 patient requiring a femoral artery cut-down because of failure of the Perclose device to deploy in the groin. Another patient had persistent venous bleeding in 1 puncture site that stopped with skin suturing. Endovascular aneurysm repair was 100% with no conversion to open surgery and no type-I endoleaks. The mean length of stay in hospital was 2.2 (SD 0.4) days. There were no long-term groin complications at 6 (SD 1) months&apos; follow-up. Conclusion: To our knowledge, this is the first Canadian report of experience with PEVAR using the Perclose device. The technique is safe, reliable and allows discharge of patients soon after surgery. Contexte : Afin de reduire la morbidite associee aux denudations au cours de la reparation d&apos;un anevrisme par voie endovasculaire, des auteurs ont suggere d&apos;utiliser la reparation endovasculaire entierement percutanee (PEVAR). Ce rapport vise a evaluer et a decrire l&apos;experience, a notre centre, de la reparation d&apos;un anevrisme de l&apos;aorte abdominale (AAA) par voie endovasculaire entierement percutanee (PEVAR). Methodes : Nous avons procede a une analyse retrospective de 15 patients consecutifs qui ont subi un AAA, dont un anevrisme de l&apos;artere iliaque commune droite. Resultats : Les 12 hommes et 3 femmes avaient en moyenne 74 (ecart-type [ET] 2) ans et ont subi une reparation PEVAR pratiquee au moyen du systeme d&apos;obturation vasculaire par suture Perclose ProGlide entre juillet 2007 et juillet 2008. Toutes les interventions chirurgicales ont ete electives. Quarante pour cent des patients avaient des antecedents de tabagisme, 73%, de l&apos;hypertension, 33%, le diabete, 20%, une maladie pulmonaire obstructive chronique et 40%, une coronaropathie. Quatorze patients avaient des dispositifs bifurques bilateraux (7 Gore Excluder bifurques, 7 greffons Cook Zenith bifurques) et 1 patient avait un dispositif Cook Zenith a deploiement unilateral. Le diametre exterieur des gaines utilisees au point de perforation s&apos;etablissait en moyenne a 18,1-Fr (ET 0,6), les corps principaux ayant 21,1-Fr (ET 0,3) et les cotes contralateraux, 15-Fr (ET 0,3). Les interventions ont reussi a 93%; il a fallu pratiquer une incision dans l&apos;artere femorale d&apos;un patient parce que le dispositif Perclose ne s&apos;etait pas deploye dans l&apos;aine. Un autre patient avait un saignement veineux persistant a un point de perforation, qui s&apos;est arrete apres la suture de la peau. La reparation de l&apos;anevrisme s&apos;est faite entierement par voie endovasculaire et il n&apos;y a eu aucune conversion en chirurgie sanglante ni aucune endofuite de type I. La duree moyenne du sejour a l&apos;hopital a ete de 2,2 (ET 0,4) jours. Il n&apos;y a eu aucune complication a long terme a l&apos;aine a 6 (ET 1) mois. Conclusion : Sauf erreur, il s&apos;agit du premier rapport canadien portant sur une experience d&apos;intervention PEVAR pratiquee avec le systeme Perclose. La technique, securitaire et fiable, permet de donner son conge au patient peu apres l&apos;intervention chirurgicale., Abdominal aortic aneurysms (AAAs) were traditionally treated with open surgical repair until the development of endovascular aneurysm repair (EVAR), as described by Parodi in 1991. (1) Since then, many studies [...]

A study was conducted to evaluate the efficacy of statin therapy to prevent adverse cardiac events after vascular surgery. Results revealed that patients who underwent vascular surgery benefited with fluvastatin therapy resulting in a reduction in postoperative cardiac outcomes.

Plasma ATP is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study investigated: 1) the role of nitric oxide (NO), prostaglandins, and adenosine as mediators of ATP-induced limb vasodilation and 2) the expression and distribution of purinergic P2 receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5-7 min of femoral intra-arterial infusion of ATP [0.45-2.45 [micro]mol/min] in 19 healthy male subjects with and without coinfusion of [N.sup.G]-monomethyl-L-arginine (L-NMMA; NO formation inhibitor; 12.3 [+ or -] 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 [+ or -] 12 [micro]g/ min), and/or theophylline (adenosine receptor blocker; 400 [+ or -] 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 [+ or -] 0.14 l/min. When ATP was coinfused with either L-NMMA, INDO, or L-NMMA + INDO combined, the increase in LBF was reduced by 14 [+ or -] 6, 15 [+ or -] 9, and 39 [+ or -] 8%, respectively (all P < 0.05), and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg [O.sub.2] extraction. Infusion of theophylline did not alter the ATP-induced leg hyperemia or systemic variables. Real-time PCR analysis of the mRNA content from the vastus lateralis muscle of eight subjects showed the highest expression of [P.sub.2Y2] receptors of the 10 investigated [P.sub.2] receptor subtypes. Immunohistochemistry showed that [P.sub.2Y2] receptors were located in the endothelium of microvessels and smooth muscle cells, whereas [P.sub.2x1] receptors were located in the endothelium and the sacrolemma. Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP-induced vasodilation in human skeletal muscle. The expression and localization of the nucleotide selective [P.sub.2Y2] and [P.sub.2x1] receptors suggest that these receptors may mediate ATP-induced vasodilation in skeletal muscle. skeletal muscle; adenosine 5'-triphosphate; purinergic receptors; nitric oxide; prostaglandins

We tested the hypothesis that aging is associated with an impaired contraction-induced rapid vasodilation in healthy adults. We reasoned that employing single contractions of a small muscle mass would allow us to isolate the local rapid vasodilatory responses independent of systemic hemodynamic and sympathetic neural influences on forearm hemodynamics. We measured forearm blood flow (Doppler ultrasound) and arterial blood pressure (Finapres) on a beat-by-beat basis and calculated the changes in forearm vascular conductance ([DELTA]FVC) in response to forearm contractions in 18 young (24 [+ or -] 1 yr) and 13 older (62 [+ or -] 2 yr) healthy subjects. Single, 1-s dynamic forearm contractions were performed with the experimental arm slightly above heart level at 5, 10, 20, and 40% of the subjects' maximal voluntary contraction (MVC) in random order. In general, muscle contractions evoked a rapid increase in FVC that reached a peak within approximately four to five cardiac cycles postcontraction in both age groups. At 5% MVC, there were no significant age-related differences in contraction-induced forearm vasodilation. However, the peak vasodilatory responses were impaired ~40-45% in older adults at 10, 20, and 40% MVC, as were the total vasodilatory responses (area under curve ~40-50%; all P < 0.05). Additionally, the immediate vasodilation (first cardiac cycle postcontraction) for the 20% and 40% MVC trials was also impaired ~50% with age (P < 0.05). There were no significant age-group differences in MVC or forearm fat-free mass, and these variables were not correlated with local vasodilation within a given exercise intensity. Under the experimental conditions employed, the blunted responses with age reflect impaired local contraction-induced rapid vasodilation. vascular control; exercise; blood flow

The extracellular matrix (ECM) plays a critical role in angiogenesis by providing biochemical and positional cues, as well as by mechanically influencing microvessel cell behavior. Considerable information is known concerning the biochemical cues relevant to angiogenesis, but less is known about the mechanical dynamics during active angiogenesis. The objective of this study was to characterize changes in the material properties of a simple angiogenic tissue before and during angiogenesis, During sprouting, there was an overall decrease in tissue stiffness followed by an increase during neovessel elongation. The fall in matrix stiffness coincided with peak matrix metalloproteinase mRNA expression and elevated proteolytic activity. An elevated expression of genes for ECM components and cell-ECM interaction molecules and a subsequent drop in proteolytic activity (although enzyme levels remained elevated) coincided with the subsequent stiffening. The results of this study show that the mechanical properties of a scaffold tissue may be actively modified during angiogenesis by the growing microvasculature, biomechanics; matrix metalloprotease

The stress and strain in the vessel wall are important determinants of vascular physiology and pathophysiology. Vessels are constrained radially by the surrounding tissue. The hypothesis in this work is that the surrounding tissue takes up a considerable portion of the intravascular pressure and significantly reduces the wall strain and stress. Ten swine of either sex were used to test this hypothesis. An impedance catheter was inserted into the carotid or femoral artery, and after mechanical preconditioning pressure-cross-sectional area relations were obtained with the surrounding tissue intact and dissected away (untethered), respectively. The radial constraint of the surrounding tissue was quantified as an effective perivascular pressure on the outer surface of the vessel, which was estimated as 50% or more of the intravascular pressure. For carotid arteries at pressure of 100 mmHg, the circumferential wall stretch ratio in the intact state was ~20% lower than in the untethered state and the average circumferential stress was reduced by ~70%. For femoral arteries, the reductions were ~15% and 70%, respectively. These experimental data support the proposed hypothesis and suggest that in vitro and in vivo measurements of the mechanical properties of vessels must be interpreted with consideration of the constraint of the surrounding tissue. stress analysis; strain; impedance planimetry; carotid artery; femoral artery

The gaseous compound carbon monoxide (CO) has been identified as an important endogenous biological messenger in brain and is a major component in regulation of celehrovascular circulation in newborns. CO is produced endogenously by catabolism of heme to CO, free iron, and biliverdin during enzymatic degradation of heme by heme oxygenase (HO). The present study was designed to test the hypothesis that endogenously produced CO contributes to hypotension-induced vasodilation of cerebral arterioles. Experiments used anesthetized piglets with implanted, closed cranial windows. Topical application of the HO substrate heme-L-lysinate caused dilation of pial arterioles that was blocked by a metal porphyrin inhibitor of HO, chromium mesoporphyrin (CrMP). In normotensive piglets (arterial pressure 64 [+ or -] 4 mmHg), CrMP did not cause vasoconstriction of pial arterioles but rather a transient dilation. Hypotension (50% of basal blood pressure) increased cerebral CO production and dilated pial arterioles from 66 [+ or -] 2 to 92 [+ or -] 7 [micro]m. In hypotensive piglets, topical CrMP or intravenous tin protoporphyrin decreased cerebral CO production and produced pial arteriolar constriction to normotensive diameters. In additional experiments, because prostacyclin and nitric oxide (NO) are also key dilators that can contribute to cerebrovascular dilation, we held their levels constant. NO/prostacyclin clamp was accomplished with continuous, simultaneous application of indomethacin, [N.sup.[omega]]-nitro-L-arginine, and minimal dilatory concentrations of iloprost and sodium nitroprusside. With constant NO and prostacyclin, the transient dilator and prolonged constrictor responses to CrMP of normotensive and hypotensive piglets, respectively, were the same as when NO and prostaglandins were not held constant. These data suggest that endogenously produced CO contributes to cerebrovascular dilation in response to reduced perfusion pressure. heme oxygenase; autoregulation; pial arterioles; newborn

Diet is a major environmental source of proinflammatory AGEs (heat-generated advanced glycation end products); its impact in humans remains unclear. We explored the effects of two equivalent diets, one regular (high AGE, H-AGE) and the other with 5-fold lower AGE (L-AGE) content on inflammatory mediators of 24 diabetic subjects: 11 in a 2-week crossover and 13 in a 6-week study. After 2 weeks on H-AGE, serum AGEs increased by 64.5% (P = 0.02) and on L-AGE decreased by 30% (P = 0.02). The mononuclear cell tumor necrosis factor-[alpha]/[beta]-actin mRNA ratio was 1.4 [+ or -] 0.5 on H-AGE and 0.9 [+ or -] 0.5 on L-AGE (P = 0.05), whereas serum vascular adhesion molecule-1 was 1,108 [+ or -] 429 and 698 [+ or -] 347 ng/ml (P = 0.01) on L- and H-AGE, respectively. After 6 weeks, peripheral blood mononuclear cell tumor necrosis factor-[alpha] rose by 86.3% (P = 0.006) and declined by 20% (P, not significant) on H- or L-AGE diet, respectively; C-reactive protein increased by 35% on H-AGE and decreased by 20% on L-AGE (P = 0.014), and vascular adhesion molecule-1 declined by 20% on L-AGE (P < 0.01) and increased by 4% on H-AGE. Serum AGEs were increased by 28.2% on H-AGE (P = 0.06) and reduced by 40% on L-AGE (P = 0.02), whereas AGE low density lipoprotein was increased by 32% on H-AGE and reduced by 33% on L-AGE diet (P < 0.05). Thus in diabetes, environmental (dietary) AGEs promote inflammatory mediators, leading to tissue injury. Restriction of dietary AGEs suppresses these effects.

An intimate study of blood flow shows why the best thing for your heart is a good beating Early in pride and Prejudice the heroine, Elizabeth Bennet, strides into her [...]

Blood vessels arise from progenitor cells, grow and branch by sprouting from preexisting vessels and remodel by splitting longitudinally. A new study proposes an additional mechanism. It seems that vascularization [...]

To the Editor: In a recent Letter in Nature Medicine, Isbell et al. (1) state that S-nitrosohemoglobin (SNO-Hb) is not essential for hypoxic vasodilation on the basis of observations in [...]

White blood cells that gobble up cellular debris also help to heal damaged blood vessels in the brain. Deqin Yang at Chongqing Medical University and Lingfei Luo at Southwest University, [...]