Resveratrol ameliorates high-glucose-induced hyperpermeability mediated by caveolae via VEGF/KDR pathway

Abstract

Endothelial hyperpermeability induced by hyperglycemia is the initial step in the development of atherosclerosis, one of the most serious cardiovascular complications in diabetes. In the present study, we investigated the effects of resveratrol (RSV), a bioactive ingredient extracted from Chinese herb rhizoma polygonum cuspidatum, on permeability in vitro and the molecular mechanisms involved. Permeability was assessed by the efflux of fluorescein isothiocyanate (FITC)-dextran permeated through the monolayer endothelial cells (ECs). The mRNA levels, protein expressions, and secretions were measured by quantitative real-time PCR, western blot, and ELISA, respectively. Increased permeability and caveolin-1 (cav-1) expression were observed in monolayer ECs exposed to high glucose. Resveratrol treatment alleviated the hyperpermeability and the overexpression of cav-1 induced by high glucose in a dose-dependent manner. b-Cyclodextrin, a structural inhibitor of caveolae, reduced the hyperpermeability caused by high glucose. Resveratrol also down-regulated the increased expressions of vascular endothelial growth factor (VEGF) and kinase insert domain receptor (KDR, or VEGF receptor-2) induced by high glucose. Inhibition of VEGF/KDR pathway by using SU5416, a selective inhibitor of KDR, alleviated the hyperpermeability and the cav-1 overexpression induced by high glucose. The above results demonstrate that RSV ameliorates caveolae-mediated hyperpermeability induced by high glucose via VEGF/KDR pathway.

Resveratrol Ameliorates High Glucose and High-Fat/Sucrose Diet-Induced Vascular Hyperpermeability Involving Cav-1/eNOS Regulation

“…Our former work found Res ameliorated hyperpermeability via VEGF/KDR pathway [41]. Additionally, investigations suggest that Res was one of the earliest identified energy-restriction mimetic agents (ERMAs) via SIRT1-dependent activation of AMPK [42], [43], and SIRT1 could activate eNOS and increase NO production and thus leads to endothelium-dependent vasodilation [44].…”

Effects of resveratrol on eNOS in the endothelium and the perivascular adipose tissue

“…Resveratrol modulates this interaction at two different levels: downregulation of Cav‐1 expression and inhibition of Cav‐1–eNOS association. These effects of resveratrol have been observed in vivo in the rat heart and in cultured endothelial cells . The downregulation of Cav‐1 (which takes hours to days) is likely to be mediated by HO‐1, whereas the acute reduction of the Cav‐1–eNOS association (which occurs within minutes) is likely to be due to Src kinase–mediated Cav‐1 phosphorylation on Tyr14 and dependent on stimulation of estrogen receptors …”

Neonatal excitotoxicity modifies blood‐brain barrier properties increasing its susceptibility to hypertonic shock in adulthood

“…In this study, we found that after neonatal MSG treatment, PV1 protein expression showed a strong tendency to increase in all studied regions in adulthood, with a significant increase in the CMC (Figure 1c). In this regard, some studies suggest that BBB disruption is more related to an increase in the endothelial transcytosis rate, rather than the loss of tight junctions (Reeson et al, 2015; Tian et al, 2013).…”