Specific induction of tie1 promoter by disturbed flow in atherosclerosis-prone vascular niches and flow-obstructing pathologies.
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.
Porat
Rinnat M
RM
Department of Molecular Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Grunewald
Myriam
M
Globerman
Anat
A
Itin
Ahuva
A
Barshtein
Gregory
G
Alhonen
Leena
L
Alitalo
Kari
K
Keshet
Eli
E
D000818:Animals; D030801:Animals, Genetically Modified; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics; D001021:Aortic Valve / Q000378:metabolism; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D017403:In Situ Hybridization; D007763:Lac Operon / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011664:Pulmonary Valve / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D042810:Receptor, TIE-1 / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow; D012160:Retina / Q000378:metabolism; D012212:Rheology; D013314:Stress, Mechanical; D014680:Veins / Q000503:physiopathology / Q000637:transplantation
D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D008156:Luciferases; D042810:Receptor, TIE-1