Abstract
BackgroundVascular shear stress promotes endothelial cell sprouting in vitro. The impact of hemodynamic forces on microRNA (miRNA) and gene expression within growing vascular networks in vivo, however, remain poorly investigated. Arteriovenous (AV) shunts are an established model for induction of neoangiogenesis in vivo and can serve as a tool for analysis of hemodynamic effects on miRNA and gene expression profiles over time.MethodsAV shunts were microsurgically created in rats and explanted on postoperative days 5, 10 and 15. Neoangiogenesis was confirmed by histologic analysis and micro-computed tomography. MiRNA and gene expression profiles were determined in tissue specimens from AV shunts by microarray analysis and quantitative real-time polymerase chain reaction and compared with sham-operated veins by bioinformatics analysis. Changes in protein expression within AV shunt endothelial cells were determined by immunohistochemistry.ResultsSamples from AV shunts exhibited a strong overexpression of proangiogenic cytokines, oxygenation-associated genes (HIF1A, HMOX1), and angiopoetic growth factors. Significant inverse correlations of the expressions of miR-223-3p, miR-130b-3p, miR-19b-3p, miR-449a-5p, and miR-511-3p which were up-regulated in AV shunts, and miR-27b-3p, miR-10b-5p, let-7b-5p, and let-7c-5p, which were down-regulated in AV shunts, with their predicted interacting targets C–X–C chemokine receptor 2 (CXCR2), interleukin-1 alpha (IL1A), ephrin receptor kinase 2 (EPHA2), synaptojanin-2 binding protein (SYNJ2BP), forkhead box C1 (FOXC1) were present. CXCL2 and IL1A overexpression in AV shunt endothelium was confirmed at the protein level by immunohistochemistry.ConclusionsOur data indicate that flow-stimulated angiogenesis is determined by an upregulation of cytokines, oxygenation associated genes and miRNA-dependent regulation of FOXC1, EPHA2 and SYNJ2BP.
Highlights
Vascular shear stress promotes endothelial cell sprouting in vitro
Expression arise already on POD 5, when functional microvasculature is not yet present around the main vessels. This finding demonstrates that alterations in molecular signaling in response to elevated blood flow occur rapidly and are already detectable when the physical outgrowth of blood vessels is still limited to intramural sprouting of new blood vessels within the vascular wall of the main vessels (Fig. 5a)
Since it is well known that endothe‐ lial nitric oxide synthase (eNOS) mediates proangiogenic effects, our results indicate that the eNOS pathway is not a main determinant of neoangiogenesis in the AV shunt model
Summary
Vascular shear stress promotes endothelial cell sprouting in vitro. The pulsatile blood flow generated by the cardiac cycle exposes endothelial cells (ECs) to two mechanical forces, namely circumferential stretch acting perpendicularly, and shear stress acting tangentially to the vascular wall [1]. In vitro studies have shown that mechanical forces acting on ECs and vascular smooth muscle cells (VSMCs) are translated into biochemical signals by mechanosensory proteins [4, 5]. These promote intracellular pathways, which lead to altered gene expression profiles [6, 7] with up-regulated proangiogenic factors like vascular endothelial growth factor (VEGF) [3]
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