Leptin-Induced Endothelium-Independent Vasoconstriction in Thoracic Aorta and Pulmonary Artery of Spontaneously Hypertensive Rats: Role of Calcium Channels and Stores.

Abstract

Decreased leptin-induced endothelium-dependent vasodilation has been reported in spontaneously hypertensive rats (SHR). Here, we report leptin-induced vasoconstriction in endothelium-denuded pulmonary artery and thoracic aorta from SHR and sought to characterize calcium handling underlying these mechanisms. Vasoreactivity to leptin was evaluated on pulmonary artery and thoracic aorta rings from 18 weeks old male SHR with or without calcium free medium, caffeine + thapsigargin + carbonyl cyanide-4-trifluoromethoxyphenylhydrazone emptying intracellular calcium stores, nifedipine a voltage-gated calcium channel inhibitor, SKF-96365 a transient receptor potential cation channels (TRPC) inhibitor, wortmaninn, a phosphatidylinositide 3-kinases (PI3K) inhibitor, or PD98059 a mitogen-activated protein kinase kinase (MAPKK) inhibitor. Calcium imaging was performed on cultured vascular smooth muscle cells incubated with leptin in presence or not of wortmaninn or PD98059. Leptin induced vasoconstriction in denuded pulmonary artery and thoracic aorta from SHR. Response was abolished when intra- or extracellular calcium stores were emptied, after blocking TRPC or voltage-dependent calcium channels or when using MAPKK or PI3K inhibitors. In vascular smooth muscle cells, leptin increased intracellular calcium. This rise was higher in SHR and abolished by MAPKK or PI3K inhibitors. TRPC6 gene expression was upregulated in arteries from SHR. Leptin-induced vasoconstriction in denuded arteries of SHR requires intracellular stores and is TRPC- and voltage-gated calcium channels dependent. Intracellular calcium increase is more pronounced in spontaneously hypertensive rats.