Endocannabinoid receptor blockade increases vascular endothelial growth factor and inflammatory markers in obese women with polycystic ovary syndrome.

Thozhukat Sathyapalan,Zeeshan Javed,Stephen L Atkin,Anne-Marie Coady,Eric S Kilpatrick

doi:10.1111/cen.13239

Abstract

Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk. To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women. Randomized, open-labelled parallel study. Endocrinology outpatient clinic in a referral centre. Twenty patients with PCOS (PCOS) and biochemical hyperandrogenaemia with a body mass index of ≥30 kg/m2 were recruited. Patients were randomized to 1·5 g daily of metformin or 20 mg daily of rimonabant. Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks of treatment. After 12 weeks of rimonabant treatment, there was a significant increase in VEGF (99·2 ± 17·6 vs 116·2 ± 15·8 pg/ml, P < 0·01) and IL-8 (7·4 ± 11·0 vs 18·1 ± 13·2 pg/ml, P < 0·05) but not after metformin (VEGF P = 0·7; IL-8 P = 0·9). There was no significant difference in the pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 following either treatment. This study suggests that rimonabant CB-I blockade paradoxically raised VEGF and the cytokine IL-8 in obese women with PCOS that may have offset the potential benefit associated with weight loss.

Highlights

Vascular endothelial growth factor (VEGF) has a crucial role in inflammation and in vascular neogenesis, in cancer [1, 2]
HOMA-β and insulin reduced with rimonabant (288 ± 150 vs. 268 ± 217, p< 0.05 and 20 ± 7 vs. 16 ± 6, p< 0.05, respectively) whilst metformin showed no effect (217 ± 104 vs. 217 ± 120 and 15 ± 9 vs. 15 ± 11, respectively). Both treatments reduced glucose levels that reflected in a significant reduction of insulin resistance from baseline for rimonabant (p
This study showed that rimonabant increased VEGF and IL8 without affecting the other proinflammatory markers in obese women with polycystic ovary syndrome (PCOS) that might not be beneficial in this group, counteracting the potential benefits associated with weight loss

Summary

Introduction

Vascular endothelial growth factor (VEGF) has a crucial role in inflammation and in vascular neogenesis, in cancer [1, 2]. Animal studies have shown that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing VEGF levels associated with a reduction in inflammatory markers [3]. Recent studies have shown that a reduction in VEGF levels may be associated with a better long term prognosis in cancer patients, with high VEGF levels being associated with a poorer prognosis [4, 5]. Our hypothesis was that rimonabant, a CB-1 specific receptor antagonist, would reduce VEGF in PCOS by a decrease in weight and reduction in inflammatory cytokines and such agents may be of potential benefit in the future. New human studies to look at this hypothesis could not be done as rimonabant was withdrawn due to side effects of depression and suicidal ideation and a retrospective analysis of a previous study was undertaken [24]

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Conclusion