Resveratrol and its synthetic derivatives exert opposite effects on mesothelial cell-dependent angiogenesis via modulating secretion of VEGF and IL-8/CXCL8

Abstract

We examined the effect of resveratrol (RVT) and its two derivatives (3,3′,4,4′-tetrahydroxy- trans -stilbene and 3,3′,4,4′,5,5′-hexahydroxy- trans -stilbene) on human peritoneal mesothelial cell (HPMC)-dependent angiogenesis in vitro. To this end, angiogenic activity of endothelial cells (HUVEC, HMVEC, and HMEC-1) was monitored upon their exposure to conditioned medium (CM) from young and senescent HPMCs treated with stilbenes or to stilbenes themselves. Results showed that proliferation and migration of endothelial cells were inhibited in response to indirect (HPMC-dependent) or direct RVT activity. This effect was associated with decreased secretion of VEGF and IL-8/CXCL8 by HPMCs treated with RVT, which confirmed the experiments with recombinant forms of these angiogenic agents. Angiogenic activity of endothelial cells treated with CM from HPMCs exposed to RVT analogues was more effective. Improved migration was particularly evident in cells exposed to CM from senescent HPMCs. Upon direct treatment, RVT derivatives stimulated proliferation (but not migration) of HUVECs, and failed to affect the behaviour of HMVEC and HMEC-1 cells. These compounds stimulated production of VEGF and IL-8/CXCL8 by HPMCs. Studies with neutralizing antibodies against angiogenic factors revealed that augmented angiogenic reactions of endothelial cells exposed to CM from HPMC treated with RVT analogues were related to enhanced production of VEGF and IL-8/CXCL8. Collectively, these findings indicate that RVT and its synthetic analogues divergently alter the secretion of the angiogenic factors by HPMCs, and thus modulate HPMC-dependent angiogenic responses in the opposite directions. This may have implications for the attempts of practical employment of the stilbenes for treatment of pathologies proceeding with abnormal vascularisation of the peritoneal tissue.

Supplementation with high-dose trans-resveratrol improves ultrafiltration in peritoneal dialysis patients: a prospective, randomized, double-blind study

“…Based on previous observations about a beneficial effect of resveratrol on anti-angiogenic responses in human peritoneal mesothelial cells (HPMCs), 12 and a hypothesis that trans-resveratrol could improve ultrafiltration via the anti-angiogenesis effect in PD-treated patients, here we tested the oral supplementation with trans-resveratrol in PD patients. To the best of our knowledge, this is the first report demonstrating the effects of trans-resveratrol on UF and neoangiogenesis in PD patients with ESRD.…”

“…Resveratrol modulates HPMCs-dependent angiogenic responses in the opposite direction via modulating the secretion of VEGF and IL-8/ CXCL8. 12 Moreover, HPMCs play an important role in peritoneal angiogenesis and fibrosis. In clinical studies, resveratrol is used orally among normal people, obese participants, and diabetes patients.…”

Antiangiogenic Activity and Pharmacogenomics of Medicinal Plants from Traditional Korean Medicine

“…Several mechanisms have been unraveled, for example, downregulation and/or inhibition of VEGF, HIF-1 α , Flk-1, and Src [68, 69]. Various signaling pathways contribute to inhibition of angiogenesis such as the eukaryotic elongation factor-2 kinase-regulated pathway, the GSK3 β / β -catenin/TCF-dependent pathway, NF- κ B-related signaling, and cytokine signaling (IL8/CXCL8) [43, 44, 70, 71]. The antiangiogenic activity of verbascoside and eriodictyol tetraacetate has not been described yet.…”

Protective Effects of Resveratrol on TNF-α-Induced Endothelial Cytotoxicity in Baboon Femoral Arterial Endothelial Cells

“…We have established a protocol for primary BAEC culture and previously performed fundamental investigations on their morphology and functions [20, 26]. Additionally, Mikula-Pietrasik et al recently demonstrated that the resveratrol and its derivatives have cell-specific effects, which were confirmed by having different effects on the proliferation of human from different sources [15]. Thus, we selected BAECs as our model for in vitro studies as a prelude to in vivo studies.…”

“…Studies of a wide range of concentrations of resveratrol administered to a uniform population of ECs are lacking. Such studies are required to comprehend the diverse and sometimes contradictory cellular effects of resveratrol [15]. Previous studies demonstrated that resveratrol has biphasic properties in relation to its concentration on EC proliferation, with no effects at low concentrations (0.1–25  μ M) and induced apoptosis at high doses (such as 100  μ M) in human umbilical vein endothelial cells (HUVECs) [16].…”