Objectives Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. However, the mechanism responsible for inducing vascular insulin resistance in prehypertension remains elusive. The present study aimed to determine whether hypoadiponectinemia causes vascular insulin resistance in prehypertension and to investigate the involved mechanisms.
Methods Four-week-age prehypertensive spontaneously hypertensive rats (ySHRs) and adiponectin knockout mice were used to evaluate the role of hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. Mesenteric arterioles were isolated from rats and mice (anaesthetised with 30 mg/kg pentobarbital sodium, i.p.), cut into 3∼4 ring segments with 1 mm long, and subjected to functional assessments.
Results Mesenteric arteriole segments of ySHRs showed a markedly reduced vasorelaxation response to insulin compared with those of age-matched Wistar-Kyoto controls (WKY) (21.6 % ± 3.2% vs. 41.6% ± 4.4% to 10-6 mol/L insulin, n = 8-10 arteriole segments from 6-8 rats, P < 0.05). Adiponectin level in serum (7.52 ± 0.86 vs. 4.89 ± 0.49 μg/ml, P < 0.05) and APPL1 expression in mesenteric arterioles of ySHRs were significantly reduced. In addition, eNOS phosphorylation and NO production in vascular tissue were markedly reduced, while ERK1/2 phosphorylation and ET-1 secretion were augmented in ySHRs. On the other hand, adiponectin knockout mice also showed significantly decreased APPL1 expression and vasodilation evoked by insulin. More importantly, treatment of ySHRs in vivo with the globular domain of adiponectin (gAd) for 1 week increased insulin-induced vasorelaxant effect (32.5% ± 2.5% vs. 21.6% ± 3.2 %, P < 0.05) and APPL1 expression in arterioles, and restored the balance between insulin-stimulated Akt/eNOS/NO and ERK1/2/ET-1 pathway. In cultured human umbilical vein endothelial cells, gAd upregulated APPL1 expression in a dose-dependent fashion. Suppression of APPL1 expression with siRNA markedly blunted the gAd’s insulin sensitisation as evidenced by reduced Akt/eNOS and potentiated ERK1/2 phosphorylation (all P < 0.05).
Conclusions Hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by reciprocally modulating the Akt/eNOS/NO and ERK1/2/ET-1 pathways in vascular endothelium in prehypertensive SHRs. Therefore, restoration of endogenous adiponectin production, supplementation with exogenous adiponectin and treatment targeting APPL1 may have potential therapeutic value in the prevention and alleviation of endothelial dysfunction and hypertension.