Key role of alpha(1)beta(1)-integrin in the activation of PI3-kinase-Akt by flow (shear stress) in resistance arteries.
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. alpha(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 alpha(1)-integrins in FMD was tested with selective antibodies and mice lacking the gene encoding for alpha(1)-integrins. Both anti-alpha(1) blocking antibodies and genetic deficiency in alpha(1)-integrin in mice (alpha(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 alpha(1)(-/-) mice than in alpha(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 alpha(1)(-/-) mice than in alpha(1)(+/+) mice. Thus alpha(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.
Loufrani
Laurent
L
UMR CNRS-INSERM 6214-771, Faculté de Medecine, 49045 Angers, France. laurent.loufrani@wanadoo.fr
Retailleau
Kevin
K
Bocquet
Arnaud
A
Dumont
Odile
O
Danker
Kerstin
K
Louis
Huguette
H
Lacolley
Patrick
P
Henrion
Daniel
D
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000906:Antibodies; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D039423:Integrin alpha1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D039222:Integrin alpha1beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D040542:Mechanotransduction, Cellular; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000109:Acetylcholine; D000906:Antibodies; D002867:Chromones; D039423:Integrin alpha1; D039222:Integrin alpha1beta1; D009025:Morpholines; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside; D010656:Phenylephrine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496315:Nos3 protein, mouse