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Background: Coronary artery disease (CAD) results from the narrowing of coronary arteries that leads to inadequate blood supply to the heart muscles, resulting in Acute Coronary Syndrome (ACS). The coronary collaterals which develop will be an alternative source of blood flow in CAD. Myocardial ischemia stimulates the development of coronary collaterals by releasing various angiogenic growth factors, like the Vascular Endothelial Growth Factor (VEGF). Serum VEGF will serve as an important biomarker in CAD; thus, it can predict coronary collateral development. Aim: To study the factors affecting the development of coronary collaterals in hypertensive and non-hypertensive patients with CAD. Methods: The study includes 100 patients who have done coronary angiography, with an average age of 60±15. Consent was obtained from all patients, and 2 ml of blood was collected. The serum VEGF concentration and cystatin-C were quantified. Coronary Angiograms, along with other reports, were collected and analyzed. CAD was diagnosed for those with ≥ 70% stenosis inany one of the major coronary artery. Coronary collateral gradings was performed as per Rentrop Scoring system. The serum VEGF and cystatin-C levels were correlated with the collateral scores and other cardiovascular risk factors. Results: A significant correlation was found between the collateral scores and serum VEGF level in hypertensive patients only. No significant correlation was found between VEGF level, collateral scores and cardiovascular risk factors. Conclusions: Cardiovascular risk factors in turn increase the serum VEGF level, which results in collateral development. Age and sex did not show show any significant association especially old age and females, with serum VEGF levels.

Abstract Background Impaired collateral formation is a major factor contributing to poor prognosis in type 2 diabetes mellitus (T2DM) patients with atherosclerotic cardiovascular disease. However, the current pharmacological treatments for improving collateral formation remain unsatisfactory. The induction of endothelial autophagy and the elimination of reactive oxygen species (ROS) represent potential therapeutic targets for enhancing endothelial angiogenesis and facilitating collateral formation. This study investigates the potential of molybdenum disulfide nanodots (MoS2 NDs) for enhancing collateral formation and improving prognosis. Results Our study shows that MoS2 NDs significantly enhance collateral formation in ischemic tissues of diabetic mice, improving effective blood resupply. Additionally, MoS2 NDs boost the proliferation, migration, and tube formation of endothelial cells under high glucose/hypoxia conditions in vitro. Mechanistically, the beneficial effects of MoS2 NDs on collateral formation not only depend on their known scavenging properties of ROS (H2O2, •O2 -, and •OH) but also primarily involve a molecular pathway, cAMP/PKA-NR4A2, which promotes autophagy and contributes to mitigating damage in diabetic endothelial cells. Conclusions Overall, this study investigated the specific mechanism by which MoS2 NDs mediated autophagy activation and highlighted the synergy between autophagy activation and antioxidation, thus suggesting that an economic and biocompatible nano-agent with dual therapeutic functions is highly preferable for promoting collateral formation in a diabetic context, thus, highlighting their therapeutic potential. Graphical Abstract

Background: Impaired collateral formation is a major factor contributing to poor prognosis in type 2 diabetes mellitus (T2DM) patients with atherosclerotic cardiovascular disease. However, the current pharmacological treatments for improving collateral formation remain unsatisfactory. The induction of endothelial autophagy and the elimination of reactive oxygen species (ROS) represent potential therapeutic targets for enhancing endothelial angiogenesis and facilitating collateral formation. This study investigates the potential of molybdenum disulfide nanodots (MoS2 NDs) for enhancing collateral formation and improving prognosis. Results: Our study shows that MoS2 NDs significantly enhance collateral formation in ischemic tissues of diabetic mice, improving effective blood resupply. Additionally, MoS2 NDs boost the proliferation, migration, and tube formation of endothelial cells under high glucose/hypoxia conditions in vitro. Mechanistically, the beneficial effects of MoS2 NDs on collateral formation not only depend on their known scavenging properties of ROS (H2O2, •O2-, and •OH) but also primarily involve a molecular pathway, cAMP/PKA-NR4A2, which promotes autophagy and contributes to mitigating damage in diabetic endothelial cells. Conclusions: Overall, this study investigated the specific mechanism by which MoS2 NDs mediated autophagy activation and highlighted the synergy between autophagy activation and antioxidation, thus suggesting that an economic and biocompatible nano-agent with dual therapeutic functions is highly preferable for promoting collateral formation in a diabetic context, thus, highlighting their therapeutic potential. [ABSTRACT FROM AUTHOR]

Background/Aims: One hallmark of chronic liver disease in patients with portal hypertension is the formation of portal-systemic collaterals in which angiogenesis has a fundamental role. We studied patients with chronic liver disease undergoing liver transplantation to correlate levels of circulating angiogenic factors in portal and peripheral circulation with portal pressure and portal-systemic collaterals. Methods: Sixteen patients who underwent liver transplantation were enrolled. During transplant surgery, we determined portal venous pressure and portal-systemic collateral formation. We determined angiogenics mediator levels in systemic and portal plasma. Peripheral plasma from healthy donors was measured as controls. Results: Vascular endothelial growth factor (VEGF)-R1 and 2, Ang-1 and 2, Tie2, FGF- 1 and 2, CD163, PDGFR-β, PDGFsRα, PDGF-AB and BB, CD163, TGF-β VASH-1 levels were significantly different in the controls in comparison to cases. Significantly decreased portal venous levels of Ang-1, FGF-1, PDGF-AB/BB, and CC were observed in patients with higher portal pressure. Peripheral VEGF, Ang-1, pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation. While peripheral VEGF-R1 was higher in patients with severe collateral formation. For portal circulation, VEGF, Ang-1, -pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation Conclusions: Angiogenesis factors correlated with portal pressure and collateral formation and different patterns of circulating angiogenesis mediators were found in peripheral and portal blood of patients with chronic liver disease. These results support the importance of angiogenic pathways in cirrhosis and portal hypertension and highlight areas for further study to identify clinically useful noninvasive markers of portal pressure and collateral formation. [ABSTRACT FROM AUTHOR]

The present retrospective study was performed to evaluate the clinical outcome, as well as post‑operative collateral formation and revascularization patterns in combined bypass. Surgical revascularization has been the mainstay of treatment for moyamoya patients. A total of 76 hemispheres from 64 moyamoya patients undergoing combined superficial temporal artery‑middle cerebral artery (STA‑MCA) anastomosis and encephalo‑duro‑myo‑synangiosis (EDMS) were retrospectively reviewed. Computed tomography perfusion and DSA were routinely performed. Modified Rankin scale (mRS) scoring and Kaplan‑Meier analysis were performed, and post‑operative collateral grading on digital subtraction angiography (DSA), reconstruction patterns and vessel diameter were measured to evaluate the revascularization area and vascular compensatory effect. During the follow‑up period, the chief complaint was partially alleviated in 57/64 patients (89.1%). In all patients, mRS was significantly decreased after the operation. Good revascularization was established in most patients at 6 months after the surgery: 92.1% of sides were scored as 2 and 77.6% were scored as 3 by post‑operative collateral grading on DSA. Dominant collateral revascularization originating from EDMS was more frequent than that from STA‑MCA anastomosis (31 vs. 19 hemispheres) at 6‑month follow‑up. Morphologically, the calibers of the STA main trunk (2.60±0.65 mm) increased profoundly at the first 10 post‑operative days (3.32±1.05 mm) and shrank back to pre‑operative status at 6 months (2.20±1.01 mm) and 12 months (2.36±0.73 mm) according to DSA examination. Middle meningeal artery (MMA) and deep temporal artery (DTA) demonstrated continuous augmentation during the follow‑up time (from 1.30±0.46 to 1.87±0.69 mm for MMA and 1.11±0.25 to 2.11±1.16 mm for DTA). These results strongly suggested that combined STA‑MCA bypass and EDMS provided efficient revascularization and reduced acute cerebral events. The direct STA‑MCA bypass provided early augmentation of cerebral perfusion, whereas the indirect EDMS provided a more durable long‑term revascularization, indicating a complementary association between the two revascularization methods. [ABSTRACT FROM AUTHOR]

Abstract: The native (pre-existing) collateral circulation minimizes tissue injury if obstructive vascular disease develops. Evidence suggests that large differences in collateral extent exist among healthy individuals, presumably from as-yet unknown genetic and/or environmental factors. Little is known regarding when or how native collaterals form—information needed to identify these factors. We examined collateral development between the middle and anterior cerebral artery trees in BALB/c and C57BL/6 mouse embryos—strains with marked differences in adult collateral density and diameter (85% fewer, 50% smaller in BALB/c). The circulation was dilated, fixed and stained. By E15.5, a “primary collateral plexus” was beginning to form in both strains. By E18.5, plexus vessel number peaked but was 60% less and diameter smaller in BALB/c (P <0.001). Earlier time points were examined to determine if these differences correlated with differences in patterning of the general circulation. At ∼E9.0, the primary capillary plexus was similar between strains, but by E12.5 branching was less and diameter larger in BALB/c (P <0.05). Between E12.5-E18.5—during pial artery tree development—small differences in tree size, branch number and distance between branches did not correlate with the large difference in collaterogenesis. Pruning of nascent collaterals between P1-P21 was comparable in both strains, yielding the adult density, but diameter and tortuosity increased less in BALB/c. Pericyte recruitment to nascent collaterals was comparable, despite lower VEGF-A and PDGF-B expression in BALB/c mice. These findings demonstrate that collaterals form late during vascular development and undergo postnatal maturation and that differences in genetic background have dramatic effects on these processes. [Copyright &y& Elsevier]

Abstract: Cell-based therapy has emerged as a promising therapeutic tool for treatment of ischemic cardiovascular disease. Both unselected bone marrow-derived mononuclear cells (BMNCs), which include stem/progenitor cells and several other cell types, and endothelial progenitor cells (EPCs), a subpopulation of BMNCs, display regenerative potential in ischemic tissue. Abundant evidence supports the involvement of EPCs in capillary growth, and EPCs also appear to participate in the formation of collateral vessels. Collectively, these effects have led to improved perfusion and functional recovery in animal models of myocardial and peripheral ischemia, and in early clinical trials, the therapeutic administration of EPCs to patients with myocardial infarction or chronic angina has been associated with positive trends in perfusion. EPCs also contribute to endothelial repair and may, consequently, impede the development or progression of arteriosclerosis. This review provides a brief summary of the preclinical and clinical evidence for the role of EPCs in blood-vessel formation and repair during ischemic cardiovascular disease. [Copyright &y& Elsevier]

The article examines the safety and effectiveness of intermittent myocardial ischemia induced by exercise on coronary collateral formation. The mechanism of collateral formation is based on the increased expression of vascular endothelial growth factor (VEGF). Appropriate intermittent myocardial ischemia induced by an exercise training protocol may facilitate coronary angiogenesis in an ischemic area via the high expression of VEGF and its receptor fetal liver kinase-1. The development of the exercise protocol with minimal ischemic burden promotes maximal collateral formation in porcine model.

Angiogenesis and coronary artery collateral formation can improve blood flow and thereby prevent myocardial ischemia. The role of perivascular fibroblasts in neovascularization remains incompletely understood. Here we investigated the effects of epicardial and myocardial fibroblasts on angiogenesis in vitro by using a serum-free microcarrier-based fibrin gel angiogenesis system. To clearly distinguish between different cell types, we either stained endothelial cells or fibroblasts in the living with 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl-indocarbocyanine-perchlorate (DiI). In cocultures, low numbers of heart fibroblasts stimulated endothelial sprouting, and capillary growth was also induced by fibroblast-conditioned media, indicating a paracrine mechanism. Capillary formation was decreased by increasing the density of fibroblasts in the cocultures, indicating contact-dependent inhibition. Using time-lapse studies, it turned out that close contacts between fibroblasts and endothelial cells resulted in rapid retraction of endothelial cells or, rarely, in cell death. Depending on the local ratio of fibroblasts to endothelial cell numbers, fibroblasts determined the location of capillary growth and the size of developing capillaries and thereby contributed to capillary network remodeling. In contrast to primary heart fibroblasts, NIH 3T3 fibroblasts did not display contact-dependent inhibition of endothelial sprouts. NIH fibroblasts were frequently seen in close association with endothelial capillaries, resembling pericytes. Contact-dependent inhibition of angiogenesis by epicardial fibroblasts could not be reversed by addition of neutralizing anti-TGF-β1 antibodies, by addition of serum, of medium conditioned by hypoxic tumor cells or myocardium, by various cytokines or by growing cocultures under hypoxic conditions. Our results implicate a pivotal role of periendothelial mesenchymal cells for the regulation of microvascular network remodeling and collateral formation. [ABSTRACT FROM AUTHOR]

SUMMARY A prospective study was performed to evaluate the sensitivity of colour Doppler flow imaging (CDFI) in the detection of occlusive arterial disease in the upper limb (using angiography as the standard) and to quantify the severity of the disease. Twenty-one ischaemic and 15 healthy limbs were studied by intra-arterial digital subtraction angiograms (IADSA) and CDFI. Selective subdavian digital subtraction angiograms were performed by the percutaneous transfemoral route. CDFI was performed from the brachial artery superiorly to the subdavian artery origin. Special attention was paid to the study of spectral waveforms and peak systolic velocities at various levels. In each subject, IADSA and CDFI were performed by different radiologists without knowledge of the results of the other investigation. In normal limbs, all arteries demonstrated a characteristic sharp triphasic spectral pattern with mean peak systolic velocity of 105, 80 and 57 cm/s for the subdavian, axillary and brachial arteries, respectively. In ischaemic limbs, reduction in peak systolic value and broadening of the spectral trace with filling in of the spectral window were noted. More characteristic was the finding of a loss of diastolic flow reversal, which was the earliest sign of significant arterial stenosis. The pattern of diastolic blood flow correlated well with the degree of collateral formation and distal vascular runoff. In conclusion, CDFI has a high sensitivity and specificity in the detection of significant arterial stenosis and is thus an ideal, inexpensive screening procedure. Analysis of the diastolic wave-form distal to the stenosis is an indicator of the degree of collateral circulation and distal runoff and thus acts as a prognostic indicator, guiding further investigation and management. [ABSTRACT FROM AUTHOR]

Targeted and sustained delivery of biologicals to improve neovascularization has been focused on stimulation angiogenesis. The formation of collaterals however is hemodynamically much more efficient, but as a target of therapy has been under-utilized. Although there is good understanding of the molecular processes involving collateral formation and there are interesting drugable candidates, the need for targeting and sustained delivery is still an obstacle towards safe and effective treatment. Molecular targeting with nanoparticles of liposomes is promising and so are peri-vascularly delivered polymer-based protein reservoirs. These developments will lead to future arteriogenesis strategies that are adjunct to current revascularization.