Specific Induction of tie1 Promoter by Disturbed Flow in Atherosclerosis-Prone Vascular Niches and Flow-Obstructing Pathologies

Abstract

Abstract-Nonlaminar flow is a major predisposing factor to atherosclerosis. Yet little is known regarding hemodynamic gene regulation in disease-prone areas of the vascular tree in vivo. We have determined spatial patterns of expression of endothelial cell receptors in the arterial tree and of reporter gene constructs in transgenic animals. In this study we show that the endothelial cell-specific receptor Tie1 is induced by disturbed flow in atherogenic vascular niches. Specifically, tie1 expression in the adult is upregulated in vascular bifurcations and branching points along the arterial tree. It is often confined to a single ring of endothelial cells functioning as sphincters and hence experiencing the steepest gradient in shear stress. In aortic valves, tie1 is asymmetrically induced only in endothelial cells encountering changes in flow direction. Disturbance of laminar flow by a surgical interposition of a vein into an artery led to induction of tie1, specifically in the region where the differently sized vessels adjoin. In pathological settings, tie1 expression is specifically induced in areas of disturbed flow because of the emergence of aneurysms and, importantly, in endothelial cells precisely overlying atherosclerotic plaques. Hemodynamic features of atherosclerotic lesion-prone regions, recreated in vitro with the aid of a flow chamber with a built-in step, corroborated an upregulated tie1 promoter activity only in cells residing where flow separation and recirculation take place. These defined promoter elements might be harnessed for targeting gene expression to atherosclerotic lesions. Key Words: angiogenesis Ⅲ atherosclerosis Ⅲ basic research Ⅲ blood flow Ⅲ blood vessels T he luminal surface of blood vessels is constantly exposed to hemodynamic forces, primarily to shear stress that is the tangential force engendered on endothelial cell surfaces by the blood flow. Hemodynamic forces play a fundamental remodeling role in the vascular network during its formative stage as well as in adapting the adult vasculature to pathophysiological changes in shear stress (eg, the process of arteriogenesis 1 ). Hemodynamic forces are also a considerable factor in the development of vascular pathologies such as atherosclerosis, aneurysms, poststenotic dilatations, and arteriovenous malformations. Notably, these diseases have the propensity to develop in vascular regions distinguished by disturbed flow that occurs naturally in certain vascular niches. Atherosclerosis, although clearly associated with some systemic risk factors, is a geometrically focal disease that preferentially develops at the outer edges of blood vessel bifurcations and at points of blood flow recirculation and stasis (eg, in aortic valves). In these predisposed locations, fluid shear stress on the vessel wall is significantly lower in magnitude and exhibits directional changes and flow separation, features absent from regions of the vascular tree generally spared from atherosclerosis. 2 The detrimental effects of disturbed flow have inspired e...

Identification and angiogenic role of the novel tumor endothelial marker CLEC14A

“…Microarray analysis of HUVEC gene expression under static and 2 Pa laminar shear stress showed CLEC14A and ROBO4 were markedly upregulated (significant false discovery rate of o12% and o1% respectively) in the absence of shear stress. Real-time PCR analysis confirmed the predicted downregulation of CLEC14A and ROBO4 expression (Figure 9a) in HUVEC exposed to 2 Pa of shear stress for 24 h. TIE1 is a validated marker of reduced shear stress at the endothelial surface (Chen-Konak et al, 2003;Porrat et al, 2004;Woo et al, 2011). Double immunofluorescence staining of TIE1 and CLEC14A showed that they co-localised on tumor vessels (Figure 9b).…”

Tied Down by Shear Force

“…These findings are thought provoking. In the context of the work of Porat et al 13 they may indicate that low levels of shear at specific arterial sites can de-repress Tie1 expression while it is persistently inhibited at other sites by higher levels of shear that routinely fluctuate with changing physiological demands for tissue perfusion. Notably, ChenKonak et al found that downregulation was accompanied by cleavage of Tie1 and binding of the endodomain to the Tie2 receptor, so Tie1 processing may have important implications for angiopoietin signaling.…”

“…In this issue of Circulation Research, Porat and colleagues 13 provide new insight into an unexpected contribution of a related RTK, Tie1, to changes in vascular structure in response to luminal hemodynamic conditions. Although sharing significant homology with Tie2, Tie1 has no known ligand, 14 and its function is very much a matter of debate.…”

“…Nonetheless, it seems inescapable that the observations of Porat and colleagues 13 To address this question, it would be of interest to determine whether its expression is increased in the classical models of chronic arterial remodeling with increases or decreases in flow. What is the significance of upregulation of Tie1 in the context of atherosclerosis and aneurysms?…”

TIE-ing off atherosclerosis

“…4 Based on those findings, H. Scott Baldwin, professor of pediatric cardiology and cell and developmental biology at Vanderbilt, hypothesized that targeting TIE1 in the adult vasculature could help treat atherosclerosis.…”