The Regulatory Functions and Signaling Pathways of Alpha- Melanocyte-Stimulating Hormone in Endothelial Cells

Abstract

alpha-melanocyte-stimulating hormone (alpha-MSH) derived from proopiomelanocortin (POMC) is well known to be a pigment-inducing peptide as well as has potent anti-inflammatory and immunomodulatory properties However the biological roles of alpha-MSH and its receptors in endothelial functions remain elusive We have previously observed that POMC gene delivery reduces tumor angiogenesis and also inhibits vascularization in rat model of osteoarthritis We also find that alpha-MSH seems to participate in the POMC-mediated anti-angiogenesis Besides POMC potently reduces the endothelial gap formation which involved in endothelial angiogenesis and permeability Therefore we speculated that alpha-MSH played an important role in endothelial functions especially angiogenesis and permeability In this study we found that alpha-MSH not only suppressed angiogenesis in vivo but also inhibited multiple angiogenic progresses including matrix metalloproteinase-2 secretion migration and tube formation of HUVECs without affecting proliferation We further clarified that alpha-MSH repressed vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expressions in endothelial cells Besides we also observed that alpha-MSH also decreased the nitric oxide (NO) production The down-regulation of NO production mediated by alpha-MSH were through reducing eNOS expression and activities as well as inhibiting NFκB activities that attenuated iNOS expression in endothelial cells We also found the expression of melanocortin-1 receptor (MC-1R) MC2-R MC-4R and MC5-R but not MC3-R in endothelial cells The antiangiogenic effects of alpha-MSH were through activating MC-1R and MC2-R that blocked VEGF/VEGFR2 and NOSs signaling in endothelial cells In addition to endothelial angiogenesis we found that alpha-MSH significantly repressed the endothelial permeability under normal conditions or hypoxia alpha-MSH also inhibited VEGF VEGFR2 eNOS and iNOS expression as well as changed endothelial tight junction formation in endothelial cells exposed to hypoxia Collectively we first unveiled the inhibitory functions of alpha-MSH on angiogenesis and permeability in endothelial cells Our experimental results also shed a new light of molecular mechanisms underlying the inhibition of POMC-mediated angiogenesis These emerging finding highlight therapeutic strategy of alpha-MSH and receptors for alleviation of endothelial angiogenesis and ischemic stroke

Date of Award	2014 Jun 18
Original language	English
Supervisor	Chao-Liang Wu (Supervisor)