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Arteriogenesis, the growth of natural bypass blood vessels, can compensate for the loss of arteries caused by vascular occlusive diseases. Accordingly, it is a major goal to identify the drugs promoting this innate immune system-driven process in patients aiming to save their tissues and life. Here, we studied the impact of the Cobra venom factor (CVF), which is a C3-like complement-activating protein that induces depletion of the complement in the circulation in a murine hind limb model of arteriogenesis. Arteriogenesis was induced in C57BL/6J mice by femoral artery ligation (FAL). The administration of a single dose of CVF (12.5 µg) 24 h prior to FAL significantly enhanced the perfusion recovery 7 days after FAL, as shown by Laser Doppler imaging. Immunofluorescence analyses demonstrated an elevated number of proliferating (BrdU+) vascular cells, along with an increased luminal diameter of the grown collateral vessels. Flow cytometric analyses of the blood samples isolated 3 h after FAL revealed an elevated number of neutrophils and platelet-neutrophil aggregates. Giemsa stains displayed augmented mast cell recruitment and activation in the perivascular space of the growing collaterals 8 h after FAL. Seven days after FAL, we found more CD68+/MRC-1+ M2-like polarized pro-arteriogenic macrophages around growing collaterals. These data indicate that a single dose of CVF boosts arteriogenesis by catalyzing the innate immune reactions, relevant for collateral vessel growth.

Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease.

This review describes the positive effects of growth hormone (GH) on the cardiovascular system. We analyze why the vascular endothelium is a real internal secretion gland, whose inflammation is the first step for developing atherosclerosis, as well as the mechanisms by which GH acts on vessels improving oxidative stress imbalance and endothelial dysfunction. We also report how GH acts on coronary arterial disease and heart failure, and on peripheral arterial disease, inducing a neovascularization process that finally increases flow in ischemic tissues. We include some preliminary data from a trial in which GH or placebo is given to elderly people suffering from critical limb ischemia, showing some of the benefits of the hormone on plasma markers of inflammation, and the safety of GH administration during short periods of time, even in diabetic patients. We also analyze how Klotho is strongly related to GH, inducing, after being released from the damaged vascular endothelium, the pituitary secretion of GH, most likely to repair the injury in the ischemic tissues. We also show how GH can help during wound healing by increasing the blood flow and some neurotrophic and growth factors. In summary, we postulate that short-term GH administration could be useful to treat cardiovascular diseases.

When tissue perfusion is impaired, the resulting reduction in O2 availability activates hypoxia-inducible factor 1 (HIF-1), which mediates increased transcription of genes encoding multiple angiogenic factors including vascular endothelial growth factor, stromal-derived factor 1, placental growth factor, and angiopoietins, leading to the mobilization of bone marrow-derived angiogenic cells, increased angiogenesis, and arterial remodeling. These HIF- 1-dependent responses are impaired by aging or loss of function mutations at the locus encoding the HIF-1α subunit. in mouse models of limb ischemia and lung transplant rejection, the augmentation of HIF-1 activity by gene therapy or chemical inducers was associated with maintenance of tissue perfusion that prevented limb amputation and allograft rejection, respectively. Thus, targeting HIF-1 may be of therapeutic benefit in these clinical contexts and others in which impaired tissue perfusion plays a role in disease pathogenesis.

Peripheral artery disease (PAD) is due to the blockage of the arteries supplying blood to the lower limbs usually secondary to atherosclerosis. The most severe clinical manifestation of PAD is critical limb ischemia (CLI), which is associated with a risk of limb loss and mortality due to cardiovascular events. Currently CLI is mainly treated by surgical or endovascular revascularization, with few other treatments in routine clinical practice. There are a number of problems with current PAD management strategies, such as the difficulty in selecting the appropriate treatments for individual patients. Many patients undergo repeated attempts at revascularization surgery, but ultimately require an amputation. There is great interest in developing new methods to identify patients who are unlikely to benefit from revascularization and to improve management of patients unsuitable for surgery. Circulating biomarkers that predict the progression of PAD and the response to therapies could assist in the management of patients. This review provides an overview of the pathophysiology of PAD and examines the association between circulating biomarkers and PAD presence, severity and prognosis. While some currently identified circulating markers show promise, further larger studies focused on the clinical value of the biomarkers over existing risk predictors are needed.

Ischemia causes an inflammatory response that is intended to restore perfusion and homeostasis yet often aggravates damage. Here we show, using conditional genetic deletion strategies together with adoptive cell transfer experiments in a mouse model of hind limb ischemia, that blood vessels control macrophage differentiation and maturation from recruited monocytes via Notch signaling, which in turn promotes arteriogenesis and tissue repair. Macrophage maturation is controlled by Notch ligand Dll1 expressed in vascular endothelial cells of arteries and requires macrophage canonical Notch signaling via Rbpj , which simultaneously suppresses an inflammatory macrophage fate. Conversely, conditional mutant mice lacking Dll1 or Rbpj show proliferation and transient accumulation of inflammatory macrophages, which antagonizes arteriogenesis and tissue repair. Furthermore, the effects of Notch are sufficient to generate mature macrophages from monocytes ex vivo that display a stable anti-inflammatory phenotype when challenged with pro-inflammatory stimuli. Thus, angiocrine Notch signaling fosters macrophage maturation during ischemia. Molecular mechanisms of macrophage-mediated regulation of artery growth in response to ischemia are poorly understood. Here the authors show that vascular endothelium controls macrophage maturation and differentiation via Notch signaling, which in turn promotes arteriogenesis and ischemic tissue recovery.

Vascular remodeling under conditions of growth or exercise, or during recovery from arterial restriction or blockage is essential for health, but mechanisms are poorly understood. It has been proposed that endothelial cells have a preferred level of fluid shear stress, or ‘set point’, that determines remodeling. We show that human umbilical vein endothelial cells respond optimally within a range of fluid shear stress that approximate physiological shear. Lymphatic endothelial cells, which experience much lower flow in vivo, show similar effects but at lower value of shear stress. VEGFR3 levels, a component of a junctional mechanosensory complex, mediate these differences. Experiments in mice and zebrafish demonstrate that changing levels of VEGFR3/Flt4 modulates aortic lumen diameter consistent with flow-dependent remodeling. These data provide direct evidence for a fluid shear stress set point, identify a mechanism for varying the set point, and demonstrate its relevance to vessel remodeling in vivo. Blood and lymphatic vessels remodel their shape, diameter and connections during development, and throughout life in response to growth, exercise and disease. This process is called vascular remodeling. The endothelial cells that line the inside of blood and lymphatic vessels are constantly exposed to the frictional force from flowing blood, termed fluid shear stress. Changes in shear stress are sensed by the endothelial cells, which trigger vascular remodeling to return the stress to the original level. It has been proposed that remodeling is governed by a preferred level of fluid shear stress, or set point, against which deviations in the shear stress are compared. Thus, changing the fluid flow through a blood vessel increases or decreases shear stress, which results in the vessel remodeling to restore the original level of shear stress. Like all remodeling, this process involves inflammation to recruit white blood cells, which assist with the process. Baeyens et al. investigated whether such a shear stress set point exists and what its biological basis might be using cultured endothelial cells from human umbilical veins. These cells remained stable and in a resting state when a particular level of shear stress was applied to them; above or below this shear stress level, the cells produced an inflammatory response like that seen during vascular remodeling. This suggests that these cells do indeed have a set point for shear stress. The same response occurred in human lymphatic endothelial cells, although in these cells the shear stress set point was much lower, correlating with the low flow in lymphatic vessels. Baeyens et al. then discovered that the shear stress set point is related to the level of a protein called VEGFR3 in the cells, which was recently found to participate in shear stress sensing. Endothelial cells from lymphatic vessels normally produce much greater quantities of VEGFR3 than those from blood vessels. Reducing the amount of VEGFR3 in lymphatic endothelial cells increased the set point shear stress, while increasing the levels in blood vessel cells decreased the set point. This suggests that the levels of this protein account for the difference in the response of these two cell types. Baeyens et al. then tested this pathway by reducing the levels of VEGFR3 in zebrafish embryos and in adult mice. In both animals, this caused arteries to narrow, showing that VEGFR3 levels also control sensitivity to shear stress—and hence vascular remodeling—inside living creatures. Understanding in detail how vascular remodeling is regulated could help improve treatments for a wide range of cardiovascular conditions. To do so, further work will be needed to develop methods to control the sensitivity of endothelial cells to shear stress and to identify other proteins that might specifically control the narrowing or the expansion of vessels in human patients.

Critical limb ischemia (CLI) constitutes the most severe form of peripheral arterial disease (PAD), it is characterized by progressive blockade of arterial vessels, commonly correlated to atherosclerosis. Currently, revascularization strategies (bypass grafting, angioplasty) remain the first option for CLI patients, although less than 45% of them are eligible for surgical intervention mainly due to associated comorbidities. Moreover, patients usually require amputation in the short-term. Angiogenic cell therapy has arisen as a promising alternative for these “no-option” patients, with many studies demonstrating the potential of stem cells to enhance revascularization by promoting vessel formation and blood flow recovery in ischemic tissues. Herein, we provide an overview of studies focused on the use of angiogenic cell therapies in CLI in the last years, from approaches testing different cell types in animal/pre-clinical models of CLI, to the clinical trials currently under evaluation. Furthermore, recent alternatives related to stem cell therapies such as the use of secretomes, exosomes, or even microRNA, will be also described.

Mouse hind limb ischemia is the most common used preclinical model for peripheral arterial disease and critical limb ischemia. This model is used to investigate the mechanisms of neovascularization and to develop new therapeutic agents. The literature shows many variations in the model, including the method of occlusion, the number of occlusions, and the position at which the occlusions are made to induce hind limb ischemia. Furthermore, predefined end points and the histopathological and radiological analysis vary. These differences hamper the correlation of results between different studies. In this review, variations in surgical methods of inducing hind limb ischemia in mice are described, and the consequences of these variations on perfusion restoration and vascular remodeling are discussed. This study aims at providing the reader with a comprehensive overview of the methods so far described, and proposing uniformity in research of hind limb ischemia in a mouse model.

Tumour blood vessels differ from their normal counterparts for reasons that have received little attention. We report here that they are of at least six distinct types, we describe how each forms, and, looking forward, encourage the targeting of tumour vessel subsets that have lost their vascular endothelial growth factor-A (VEGF-A) dependency and so are likely unresponsive to anti-VEGF-A therapies.