Differential gene expression by endothelial cells under positive and negative streamwise gradients of high wall shear stress

Abstract

, and flow acceleration and deceleration in the branches create positive and negative streamwise gradients in WSS (WSSG), respectively. Intracranial aneurysms tend to form in regions with high WSS and positive WSSG. However, little is known about the responses of endothelial cells (ECs) to either positive or negative WSSG under high WSS conditions. We used cDNA microarrays to profile gene expression in cultured ECs exposed to positive or negative WSSG for 24 h in a flow chamber where WSS varied between 3.5 and 28.4 Pa. Gene ontology and biological pathway analysis indicated that positive WSSG favored proliferation, apoptosis, and extracellular matrix processing while decreasing expression of proinflammatory genes. To determine if similar responses occur in vivo, we examined EC proliferation and expression of the matrix metalloproteinase ADAMTS1 under high WSS and WSSG created at the basilar terminus of rabbits after bilateral carotid ligation. Precise hemodynamic conditions were determined by computational fluid dynamic simulations from three-dimensional angiography and mapped on immunofluorescence staining for the proliferation marker Ki-67 and ADAMTS1. Both proliferation and ADAMTS1 were significantly higher in ECs under positive WSSG than in adjacent regions of negative WSSG. Our results indicate that WSSG elicits distinct EC gene expression profiles and particular biological pathways including increased cell proliferation and matrix processing. Such EC responses may be important in understanding the mechanisms of intracranial aneurysm initiation at regions of high WSS and positive WSSG. high wall shear stress; microarray; intracranial aneurysm initiation; vascular remodeling; spatial gradient AS THE INNERMOST LINING OF the blood vessel wall, endothelial cells (ECs) are the signal transduction interface between wall shear stress (WSS) exerted on the lining by flowing blood and the responses of underlying tissue. It is well known that endothelial structure, function, and gene expression are modulated by normal WSS (1.5-2.5 Pa) and that ECs respond differently when exposed to relatively low WSS (Ͻ0.4 Pa), and this effect is believed to play a role in atherosclerosis (21). However, endothelial responses under considerably higher WSS (Ͼ10 Pa) are not well characterized. Such high WSS occurs in arteries feeding arteriovenous fistulas (37, 42), in stenosed vessels (33, 34), in collateral arteries secondary to blockage (36, 50), and at arterial bifurcations, where high WSS predisposes intracranial vessels to aneurysm formation (24, 26).There is mounting evidence that ECs are also sensitive to spatial differences in WSS over their luminal surface, specifically to streamwise gradients in WSS [WSS gradient (WSSG)]. The effects of WSSG under low WSS have been examined in vitro in flow recirculation zones, which in vivo are prone to atherogenesis (10, 56). Under low WSS and WSSG, ECs show increased permeability (31), migration (5, 46), proliferation (46), and activation of the transcription factors NF-B, Egr-1, c-Jun, an...

Precision Medicine in Critical Illness: Sepsis and Acute Respiratory Distress Syndrome

“…Genes that are expressed exclusively by endothelium, epithelium, stromal tissue, or tissue specific to the infected organ will not be captured by whole blood or leukocyte gene expression profiling. Though there may be strong interest to evaluate vascular mRNA, a vessel biopsy will remain highly unlikely and circulating endothelial cells are difficult to collect and may be fundamentally distinct compared to intact vasculature [83]. For ARDS, there is general consensus that lung tissue would provide the maximal utility for gene, protein, and metabolite expression.…”

TIMP3 is Regulated by Pericytes upon Shear Stress Detection Leading to a Modified Endothelial Cell Response

“…Others have reported that ECs subjected to shear can upregulate ADAMTS-1. 15,16 Both ADAMTS-1 transcript ( Fig. 2D) and protein ( Fig.…”

“…13,14 One metalloproteinase, a disintegrin and metalloproteinase with thrombospondin motif-1 (ADAMTS-1), which is crucial for vascular regression has been found to be upregulated under shear stress in ECs. 15,16 Furthermore, ADAMTS-1 is abundant in human vulnerable carotid lesions. 17,18 These results imply that ADAMTS-1 might play a key role in atherosclerotic processes.…”

Computational Fluid Dynamics and Cerebral Aneurysms

“…One motivation for the utilization of computational techniques to visualize and quantify aneurysm hemodynamics is the fact that hemodynamic factors have long been suspected to be associated with aneurysm formation or rupture (Cebral et al 2005;Castro et al 2006;Dempere-Marco et al 2006;Di Martino et al 2001;Hoi et al 2006;Jou et al 2003;Karmonik et al 2006Karmonik et al , 2008aMantha et al 2006;Steinman et al 2003) but that standard clinical in vivo imaging techniques have PanVascular Medicine DOI 10.1007/978-3-642-37393-0_33-1 # Springer-Verlag Berlin Heidelberg 2014 limited the accessibility of these parameters to direct measurement. In particular, wall shear stress (WSS) has emerged as a parameter of interest as endothelial cells are reported to sense WSS variations (Dolan et al 2013a). High WSS (typically >3 Pa) has emerged as a key regulator of vascular biology and pathology.…”