Journal of Vascular Research最新文献

Introduction: Peripheral arterial disease (PAD) occurs from atherosclerotic obstruction of arteries in the lower extremities. Restoration of perfusion requires angiogenesis and arteriogenesis through migration and differentiation of endothelial progenitor cells (EPCs) and macrophages at the site of injury. The time of recruitment has not been fully investigated. In this study, we investigated the infiltration of these cells in murine hind limb ischemia (HLI) model of PAD.

Methods: EPCs and M1-like and M2-like macrophages from ischemic skeletal muscles were quantified by flow cytometry at day-0, 1, 3, 7, and 14 post-HLI.

Results: The abundance of EPCs increased from day 1 and was highest on day 7 until day 14. M1-like population similarly increased and was highest on day 14 during the experiment. M2-like population was significantly greater than M1-like at baseline but surpassed the highest value of M1-like by day 7 during the experiment. Muscle regeneration and capillary density also increased and were highest at days 3 and 7, respectively, during the experiment. All mice achieved near full perfusion recovery by day 14.

Conclusion: Thus, we observed a gradual increase in the percentage of EPC's and this was temporally paralleled with initial increase in M1-like followed by sustained increased in M2-like macrophages and perfusion recovered post-HLI.

Background: Indoxyl sulfate (IS) is a protein-bound uremic toxin with vascular toxicity. The primary cause of death in uremic patients on maintenance hemodialysis is vascular disease, and it had been reported that vascular smooth muscle cells (VSMCs) trans-differentiation (VT) plays a vital role in the context of vascular diseases, but the underlying mechanisms remain obscure. Thrombospondin-1 (TSP-1) participates in vascular calcification by keeping the balance of extracellular matrix, but its role in IS-induced VT is unclear.

Methods: In this study, clinical specimens, animal models, and in vitro VSMCs were used to investigate the role of TSP-1 in IS induced VT and the potential therapeutic methods.

Results: We found that TSP-1 was significantly decreased in arterial samples from uremic patients, animal models, and in VSMCs after IS treatment. Downregulation of TSP-1 sufficiently induced the trans-differentiation genotypes of VSMCs.

Conclusion: Emodin, the main monomer extracted from rhubarb, could alleviate IS-induced VT in vitro by upregulating TSP-1. Taken together, IS induces VT by downregulating TSP-1. Emodin might be a candidate drug to alleviate VT under IS treatment.

Connexin 43 (Cx43) is essential to the function of the vasculature. Cx43 proteins form gap junctions that allow for the exchange of ions and molecules between vascular cells to facilitate cell-to-cell signaling and coordinate vasomotor activity. Cx43 also has intracellular signaling functions that influence vascular cell proliferation and migration. Cx43 is expressed in all vascular cell types, although its expression and function vary by vessel size and location. This includes expression in vascular smooth muscle cells (vSMC), endothelial cells (EC), and pericytes. Cx43 is thought to coordinate homocellular signaling within EC and vSMC. Cx43 gap junctions also function as conduits between different cell types (heterocellular signaling), between EC and vSMC at the myoendothelial junction, and between pericyte and EC in capillaries. Alterations in Cx43 expression, localization, and post-translational modification have been identified in vascular disease states, including atherosclerosis, hypertension, and diabetes. In this review, we discuss the current understanding of Cx43 localization and function in healthy and diseased blood vessels across all vascular beds.

Control of vascular cell growth responses is critical for development and maintenance of a healthy vasculature. Connexins - the proteins comprising gap junction channels - are key regulators of cell growth in diseases such as cancer, but their involvement in controlling cell growth in the vasculature is less well appreciated. Connexin37 (Cx37) is one of four connexin isotypes expressed in the vessel wall. Its primary role in blood vessels relies on its unique ability to transduce flow-sensitive signals into changes in cell cycle status of endothelial (and perhaps, mural) cells. Here, we review available evidence for Cx37's role in the regulation of vascular growth, vessel organization, and vascular tone in healthy and diseased vasculature. We propose a novel mechanism whereby Cx37 accomplishes this with a phosphorylation-dependent transition between closed (growth-suppressive) and multiple open (growth-permissive) channel conformations that result from interactions of the C-terminus with cell-cycle regulators to limit or support cell cycle progression. Lastly, we discuss Cx37 and its downstream signaling as a novel potential target in the treatment of cardiovascular disease, and we address outstanding research questions that still challenge the development of such therapies.

Introduction: Physiological system complexity represents an imposing challenge to gaining insight into how arteriolar behavior emerges. Further, mechanistic complexity in arteriolar tone regulation requires that a systematic determination of how these processes interact to alter vascular diameter be undertaken.

Methods: The present study evaluated the reactivity of ex vivo proximal and in situ distal resistance arterioles in skeletal muscle with challenges across the full range of multiple physiologically relevant stimuli and determined the stability of responses over progressive alterations to each other parameter. The five parameters chosen for examination were (1) metabolism (adenosine concentration), (2) adrenergic activation (norepinephrine concentration), (3) myogenic activation (intravascular pressure), (4) oxygen (superfusate PO2), and (5) wall shear rate (altered intraluminal flow). Vasomotor tone of both arteriole groups following challenge with individual parameters was determined; subsequently, responses were determined following all two- and three-parameter combinations to gain deeper insight into how stimuli integrate to change arteriolar tone. A hierarchical ranking of stimulus significance for establishing arteriolar tone was performed using mathematical and statistical analyses in conjunction with machine learning methods.

Results: Results were consistent across methods and indicated that metabolic and adrenergic influences were most robust and stable across all conditions. While the other parameters individually impact arteriolar tone, their impact can be readily overridden by the two dominant contributors.

Conclusion: These data suggest that mechanisms regulating arteriolar tone are strongly affected by acute changes to the local environment and that ongoing investigation into how microvessels integrate stimuli regulating tone will provide a more thorough understanding of arteriolar behavior emergence across physiological and pathological states.

Introduction: Cerebral blood flow (CBF) is reduced in patients with Alzheimer's disease (AD). Flow-mediated dilation (FMD), which plays a key role in the regulation of blood flow, is attenuated by endothelin-1. We hypothesized that endothelin receptor blockade may improve CBF in AD.

Methods: We investigated cerebrovascular reactivity in a mouse model of AD (APP-PS1; 5-6-month-old male subjects). We assessed the in vivo response to normoxic hypercapnia and in vitro FMD in isolated cerebral and mesenteric resistance arteries before and after endothelin receptor blockade (bosentan).

Results: Normoxic hypercapnia increased basilar trunk blood flow velocity (+12.3 ± 2.4%; p = 0.006, n = 6) in wild-type (WT) mice but reduced blood flow in APP-PS1 mice (-11.4 ± 1.2%; p < 0.0001, n = 8). Bosentan (50 mg/kg, acute intraperitoneal injection) restored cerebrovascular reactivity in APP-PS1 mice (+10.2 ± 2.2%; p < 0.0001, n = 8) but had no effect in WT. FMD was reduced in the posterior cerebral artery of APP-PS1 compared to WT and was normalized by bosentan (1 μmol/L, 30 min, or 50 mg/kg/day for 28 days). FMD was similar in the mesenteric artery of APPS-PS1 and WT.

Conclusion: APP-PS1 mice exhibited cerebrovascular endothelial dysfunction. Acute and chronic blockade of endothelin receptors restored endothelial vasomotor function, suggesting a promising therapeutic approach to restoring cerebral vasoreactivity in AD.

Introduction: Cardiovascular disorders are characterized by vascular smooth muscle (VSM) transition from a contractile to proliferative state. Protease-activated receptor 2 (PAR2) involvement in this phenotypic conversion remains unclear. We hypothesized that PAR2 controls VSM cell proliferation in phenotype-dependent manner and through specific protein kinases.

Methods: Rat clonal low (PLo; P3-P6) and high passage (PHi; P10-P15) VSM cells were established as respective models of quiescent and proliferative cells, based on reduced PKG-1 and VASP. Western blotting determined expression of cytoskeletal/contractile proteins, PAR2, and select protein kinases. DNA synthesis and cell proliferation were measured 24-72 h following PAR2 agonism (SLIGRL; 100 nM-10 μm) with/without PKA (PKI; 10 μm), MEK1/2 (PD98059; 10 μm), and PI3K (LY294002; 1 μm) blockade.

Results: PKG-1, VASP, SM22α, calponin, cofilin, and PAR2 were reduced in PHi versus PLo cells. Following PAR2 agonism, DNA synthesis and cell proliferation increased in PLo cells but decreased in PHi cells. Western analyses showed reduced PKA, MEK1/2, and PI3K in PHi versus PLo cells, and kinase blockade revealed PAR2 controls VSM cell proliferation through PKA/MEK1/2.

Discussion: Findings highlight PAR2 and PAR2-driven PKA/MEK1/2 in control of VSM cell growth and provide evidence for continued investigation of PAR2 in VSM pathology.

Vascular system is a complex network in which different cell types and vascular segments must work in concert to regulate blood flow distribution and arterial blood pressure. Although paracrine/autocrine signaling is involved in the regulation of vasomotor tone, direct intercellular communication via gap junctions plays a central role in the control and coordination of vascular function in the microvascular network. Gap junctions are made up by connexin (Cx) proteins, and among the four Cxs expressed in the cardiovascular system (Cx37, Cx40, Cx43, and Cx45), Cx40 has emerged as a critical signaling pathway in the vessel wall. This Cx is predominantly found in the endothelium, but it is involved in the development of the cardiovascular system and in the coordination of endothelial and smooth muscle cell function along the length of the vessels. In addition, Cx40 participates in the control of vasomotor tone through the transmission of electrical signals from the endothelium to the underlying smooth muscle and in the regulation of arterial blood pressure by renin-angiotensin system in afferent arterioles. In this review, we discuss the participation of Cx40-formed channels in the development of cardiovascular system, control and coordination of vascular function, and regulation of arterial blood pressure.

Objective: The aim of the study was to evaluate the effect of the RhoA/ROCK inhibitor Fasudil on retinal neovascularization (NV) in vivo and angiogenesis in vitro.

Methods: C57BL/6 was used to establish an OIR model. First, RhoA/ROCK expression was first examined and compared between OIR and healthy controls. Then, we evaluated the effect of Fasudil on pathological retinal NV. Whole-mount retinal staining was performed. The percentage of NV area, the number of neovascular tufts (NVT), and branch points (BP) were quantified. Finally, human umbilical vein endothelial cells (HUVECs) were used to investigate the effect of Fasudil on angiogenesis.

Results: Real-time PCR and Western blotting showed that ROCK expression in retinal tissue was statistically upregulated in OIR. Furthermore, we found that Fasudil attenuated the percentage of NV area, the number of NVT, and BP significantly. In addition, Fasudil could suppress the proliferation and migration of HUVECs induced by VEGF.

Conclusions: RhoA/ROCK might be involved in the pathogenesis of OIR. And its inhibitor Fasudil could suppress retinal NV in vivo and angiogenesis in vitro. Fasudil may be a potential treatment strategy for retinal vascular diseases.