Disruption of membrane caveolae limits pulmonary vasoconstriction induced by agonists in pulmonary hypertension rats (1089.8)

Abstract

A rise in cytosolic Ca2+ in pulmonary artery smooth muscle cells (PASMCs) is the major trigger for pulmonary vasoconstriction. Previous studies of pulmonary hypertension (PH) show that canonical transient receptor potential (TRPC) is an important constituent of store‐operated Ca2+ channel (SOCC); TRPC genes are upregulated and store‐operated Ca2+ entry (SOCE) is augmented in PASMCs of monocrotaline (MCT)‐treated and chronic hypoxic (CH) rats. Since TRPC and caveolin may functionally colocalize in caveolae in PASMCs and coordinate to regulate pulmonary vascular tone, we sought to examine the effects of caveolae disruption on agonist‐induced contraction of isolated pulmonary arteries (PAs) of CH‐ and MCT‐induced PH rats. Rats developed severe PH and right ventricular hypertrophy within three weeks after CH‐(10% O2) exposure or single intraperitoneal injection of MCT at a dose of 60 mg/kg. The tension of PA rings induced by various agonists were compared with and without the caveolae‐disrupting agent methyl‐beta‐cyclodextrin (MCD) or cholesterol repletion with a cholesterol:MCD mixture (1:5). The MCD‐pretreatment attenuated PA contraction induced by cyclopiazonic acid (CPA), endothelin‐1(ET‐1) and phenylephrine (PE), but had no effect on KCl‐induced vasoconstriction in control groups. The cholesterol:MCD mixture rescued PA‐contraction induced by CPA, ET‐1 and PE. Compared with the control group, MCD‐pretreatment resulted in further inhibition of the CPA‐induced contraction of PAs of both CH‐ and MCT‐treated rats, as well as the PE‐induced contraction of PAs of MCT‐treated rats, but had no effect on KCl‐induced contraction in the CH‐ and MCT‐ groups. These results suggest that the activity of voltage‐dependent Ca2+ channels does not depend on the integrity of associated with caveolae, but the SOCC may be closely associated with the cholesterol‐enriched membrane lipid domains of PAs. Moreover, the enhanced SOCE of PAs caveolae in PH rats.Grant Funding Source: NSFC31171104 and FJMU09ZD010