Abstract
Resistance arteries are the site of the earliest manifestations of many cardiovascular and metabolic diseases. Flow 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. Integrin (a1-b1), 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 a1-b1 integrins in FMD was tested using selective antibodies and mice lacking the gene encoding for a1 integrins. Both anti-b1 blocking antibodies and the genetic deficiency in a1-integrin in mice (a1-/-) inhibited FMD without affecting receptor-mediated (acetylcholine) endothelium-dependent dilation or endothelium independent dilation. Similarly, vasoconstrictor tone (myogenic tone and phenylephrine contraction) was not affected. In MRA phosphorylated-Akt and PI3-kinase were significantly lower in a1-/- mice than in a1-/- mice, although Akt and eNOS were not affected. Pharmacological blockade of the PI3kinase-Akt pathway with LY294002 inhibited FMD. This inhibitory effect of LY294002 was significantly lower in a1-/- mice than in a1+/+ mice. Thus, a1 integrin has a key role in FMD in resistance arteries by transmitting the signal to eNOS through activation of PI3-kinase and Akt. Due to the central role of flow activation of the endothelium in vascular disorders this finding opens new perspectives in the pathophysiology of the microcirculation and provides new therapeutic targets.
Published Version
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