Vascular insulin resistance in prehypertensive rats: Role of PI3-kinase/Akt/eNOS signaling

It is well known that systemic insulin resistance is closely associated with the metabolic syndrome including type 2 diabetes and hypertension. However, it remains unclear whether vascular insulin resistance acts as an early etiologic factor for the development of hypertension. Male spontaneously hypertensive rats (SHRs) aged 5 weeks (young) and 15 weeks (adult) were studied and vascular insulin resistance was assessed as the function of isolated aortic vasodilatory response to insulin in vitro. Compared with Wistar–Kyoto (WKY) rats, adult SHRs exhibited significant hypertension with significantly decreased aortic vasodilatation to insulin, whereas young SHRs had normal blood pressure but exhibited similar vascular insulin resistance. Both young and adult SHRs showed significant downregulated expression of PI3-kinase and decreased insulin-stimulated phosphorylations of Akt and eNOS in vascular tissues. Treatment with rosiglitazone (RSG), an insulin sensitizer, for 2 weeks increased vascular PPARγ expression and restored PI3-kinase/Akt/eNOS-mediated signaling pathway only in young SHRs. More importantly, this treatment improved aortic vasodilatory response to insulin in young but not in adult SHRs. In summary, vascular insulin resistance, characterized by the impairment of PI3-kinase/Akt/eNOS-mediated signaling in vascular endothelium, may play important roles in endothelial dysfunction and subsequent development of hypertension in normotensive young SHRs.