HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/H1906    most recent 00966.2006v2 00966.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Loufrani, L. Articles by Henrion, D. Search for Related Content PubMed PubMed Citation Articles by Loufrani, L. Articles by Henrion, D.

Key role of ₁β₁-integrin in the activation of PI3-kinase-Akt by flow (shear stress) in resistance arteries

¹Centre National de la Recherche Scientifique UMR 6214, Institut National de la Santé et de la Recherche Médicale (INSERM) 771, University of Angers, Angers and ³INSERM U684, Nancy, France; and ²University Medical Center Charité, Berlin, Germany

Submitted 6 September 2006 ; accepted in final form 24 January 2008

Resistance arteries are the site of the earliest manifestations of many cardiovascular and metabolic diseases. Flow (shear stress) is the main physiological stimulus for the endothelium through the activation of vasodilatory pathways generating flow-mediated dilation (FMD). The role of FMD in local blood flow control and angiogenesis is well established, and alterations in FMD are early markers of cardiovascular disorders. ₁-Integrin, which has a role in angiogenesis, could be involved in FMD. FMD was studied in mesenteric resistance arteries (MRA) isolated in arteriographs. The role of ₁-integrins in FMD was tested with selective antibodies and mice lacking the gene encoding for ₁-integrins. Both anti-₁ blocking antibodies and genetic deficiency in ₁-integrin in mice (₁^–/–) inhibited FMD without affecting receptor-mediated (acetylcholine) endothelium-dependent dilation or endothelium-independent dilation (sodium nitroprusside). Similarly, vasoconstrictor tone (myogenic tone and phenylephrine-induced contraction) was not affected. In MRA phosphorylated Akt and phosphatidylinositol 3-kinase (PI3-kinase) were significantly lower in ₁^–/– mice than in ₁^+/+ mice, although total Akt and endothelial nitric oxide synthase (eNOS) were not affected. Pharmacological blockade of PI3-kinase-Akt pathway with LY-294002 inhibited FMD. This inhibitory effect of LY-294002 was significantly lower in ₁^–/– mice than in ₁^+/+ mice. Thus ₁-integrin has a key role in flow (shear stress)-dependent vasodilation in resistance arteries by transmitting the signal to eNOS through activation of PI3-kinase and Akt. Because of the central role of flow (shear stress) activation of the endothelium in vascular disorders, this finding opens new perspectives in the pathophysiology of the microcirculation and provides new therapeutic targets.

myogenic tone; nitric oxide; N^G-nitro-L-arginine methyl ester; Akt; ₁-integrin; transgenic mice; mechanotransduction

This article has been cited by other articles:

				F. Morello, A. Perino, and E. Hirsch Phosphoinositide 3-kinase signalling in the vascular system Cardiovasc Res, May 1, 2009; 82(2): 261 - 271. [Abstract] [Full Text] [PDF]

				M. E. Hartnett, D. Martiniuk, G. Byfield, P. Geisen, G. Zeng, and V. L. Bautch Neutralizing VEGF Decreases Tortuosity and Alters Endothelial Cell Division Orientation in Arterioles and Veins in a Rat Model of ROP: Relevance to Plus Disease Invest. Ophthalmol. Vis. Sci., July 1, 2008; 49(7): 3107 - 3114. [Abstract] [Full Text] [PDF]