Abstract 5535: Vascular Insulin Resistance in Prehypertensive Rats Contributes to the Development of Hypertension: Role of PI3 Kinase/Akt/Enos Signaling
Objective: It is well known that systemic insulin resistance (IR) is closely associated with metabolic syndrome including type 2 diabetes and hypertension. However, it remains unclear whether vascular IR acts as an early etiologic factor for the development of hypertension. The present study aimed to test the hypothesis that vascular IR in the conduit arteries contributes to the pathogenesis of hypertension in hypertension-prone normotensive rats, and to further investigate the underlying mechanism.
Methods: Male spontaneously hypertensive rats (SHRs) aged 5-weeks (young) and 15-weeks (adult) were studied and vascular IR was assessed as the function of isolated aortic vasodilatory response to insulin in vitro.
Results: Compared with Wistar-Kyoto (WKY) rats, adult SHRs exhibited significant hypertension (systolic blood pressure, 173±4 vs. 121±4 mmHg in adult WKY, n = 8, P<0.01) with significantly decreased aortic vasodilatation to insulin (38.7±4.4% vs. 70.9±3.6%, n = 8 –10 aortic segments/group from 5–7 rats, P<0.01), whereas young SHRs had normal blood pressure (121±2 vs. 114±4 mmHg in young WKY, P>0.05) but exhibited similar vascular IR (42.3±5.2% vs. 68.5±5.9%, P<0.01). Both young and adult SHRs showed significant downregulated expression of PI3-Kinase and decreased insulin-stimulated phosphorylations of Akt and eNOS in vascular tissues (n = 3, P<0.01). More importantly, treatment with rosiglitazone (RSG), an insulin sensitizer, for 2 wks increased vascular PPARγ expression and restored PI3-Kinase/Akt/eNOS-mediated signaling pathway induced by insulin, thus improved aortic vasodilatory response to insulin in young but not in adult SHRs (P<0.05).
Conclusion: Vascular IR, characterized by the impairment of PI3-Kinase/Akt/eNOS signaling in vascular endothelium, may play a role in endothelial dysfunction and subsequent development of hypertension in normotensive young SHRs.