Chronic Hypoxia Attenuates Endothelium‐dependent Hyperpolarization‐induced Vascular Relaxation in Pulmonary Artery and Leads to Pulmonary Hypertension

Abstract

Endothelial cell dysfunction is implicated in the development and progression of many cardiovascular diseases including pulmonary hypertension (PH). It has been well documented that endothelium‐dependent relaxation (EDR) is attenuated due to decreased NO bioavailability in pulmonary artery (PA) of PH model animals; however there is few report investigating the role of endothelium‐dependent hyperpolarization (EDH)‐mediated vascular relaxation in PH. In this study, we examined the role of chronic hypoxia on EDH‐induced pulmonary arterial relaxation with a special focus on connexin 40 (Cx40). Connexins are a group of membrane proteins that form gap junctions between the cells and serve as a tunnel during electrical propagation (e.g., hyperpolarization). Cx40 is predominantly expressed in vascular endothelial cells (ECs). We first examined vasorelaxant properties in the different size of PAs dissected from wild type (Wt) and Cx40 knockout (KO) mice. There was no difference of acetylcholine (ACh)‐induced relaxation (i.e., EDR) in second order of PAs between Wt mice and Cx40 KO mice, while EDR was significantly attenuated in the fourth order of PAs of Cx40 KO mice compared to the Wt mice. In the second order of PAs, we did not observe EDH‐dependent vascular relaxation in both Wt and Cx40 KO mice. In the fourth order of PAs, strong EDH‐dependent relaxation was observed in Wt mice and it was significantly reduced in Cx40 KO mice. Cx40 KO mice exhibited a significant increase in right ventricle systolic pressure (RVSP) compared to Wt mice. Chronic hypoxia (10% O2, 4 weeks) increased RVSP in both Wt and Cx40 KO mice and Cx40 KO mice exposed to hypoxia exhibited significantly higher RVSP than Wt mice exposed to hypoxia. Furthermore, chronic hypoxia attenuated EDR and EDH‐dependent relaxation in the fourth order of PAs from Wt mice; however, there was no difference of EDR and EDH‐dependent relaxation in the fourth order of PAs in Cx40 KO mice. Mouse pulmonary endothelial cells isolated from hypoxia‐exposed Wt mice exhibited significant decrease in Cx40 protein level compared to Wt mice exposed to normoxia. These data suggest that chronic hypoxia decreases Cx40 protein expression and attenuates EDH in small PAs that subsequently leads to increase in pulmonary arterial resistance and develops pulmonary hypertension.Support or Funding InformationNIH R01HL115578This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.