Abstract
Pulmonary arterial hypertension (PAH) is a chronic condition characterized by vascular remodeling and increased vaso-reactivity. PAH is more common in females than in males (~3:1). Connexin (Cx)43 has been shown to be involved in cellular communication within the pulmonary vasculature. Therefore, we investigated the role of Cx43 in pulmonary vascular reactivity using Cx43 heterozygous (Cx43+/−) mice and 37,43Gap27, which is a pharmacological inhibitor of Cx37 and Cx43. Contraction and relaxation responses were studied in intra-lobar pulmonary arteries (IPAs) derived from normoxic mice and hypoxic mice using wire myography. IPAs from male Cx43+/− mice displayed a small but significant increase in the contractile response to endothelin-1 (but not 5-hydroxytryptamine) under both normoxic and hypoxic conditions. There was no difference in the contractile response to endothelin-1 (ET-1) or 5-hydroxytryptamine (5-HT) in IPAs derived from female Cx43+/−mice compared to wildtype mice. Relaxation responses to methacholine (MCh) were attenuated in IPAs from male and female Cx43+/− mice or by pre-incubation of IPAs with 37,43Gap27. Nω-Nitro-L-arginine methyl ester (l-NAME) fully inhibited MCh-induced relaxation. In conclusion, Cx43 is involved in nitric oxide (NO)-induced pulmonary vascular relaxation and plays a gender-specific and agonist-specific role in pulmonary vascular contractility. Therefore, reduced Cx43 signaling may contribute to pulmonary vascular dysfunction.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive disease in which the mean resting pulmonary artery pressure rises above 25 mmHg with a mean resting capillary wedge pressure lower than 15 mmHg [1]
Gene expression of Connexins 37 (Cx37), Cx40, Cx45, and Panx1 was assessed in pulmonary arteries from Cx43+/− mice along with gene expression of various mediators known to play a role in the development of PAH: tryptophan hydroxylase 1 (Tph1), endothelial nitric oxide synthase, and bone morphogenetic receptor type II (BMPRII, encoded by BMPR2)
Cx43 expression was higher in tfhemanaleins tmhaanleisn minalbeostihn bWoTth aWnTd aCnxd4C3+x/−43m+/i−cem(iFceig(uFriegu1rAe 1).AA).fAtefrtwerawrdar,dp, uplumlmonoanrayryaarrteterriaiall ggeennee eexxpprreessssiioonn lleevveellss ooff CCxx4433 wwiitthh CCxx3377, CCxx4400, aanndd CCxx4455 iinn wwiillddttyyppee mmiiccee wweerree ccoommppaarreedd
Summary
Pulmonary arterial hypertension (PAH) is a progressive disease in which the mean resting pulmonary artery pressure rises above 25 mmHg with a mean resting capillary wedge pressure lower than 15 mmHg [1]. Pannexin-1 (Panx1) is expressed throughout the vasculature in the endothelium and in the medial layer of small resistance arteries [13] and has been shown to play an important role in the α-adrenoceptor mediated contractile response [14]. The nitric oxide synthase (NOS) inhibitor asymmetric dimethyl arginine (ADMA), is upregulated in PAH patients and inhibits gap junctional communication in human PAECs. The effects of ADMA are prevented by over-expression of Cx43 or by treatment with rotigaptide, which enhances connexin coupling [15]. Gene expression of Cx37 (encoded by GJA4), Cx40 (encoded by GJA5), Cx45 (encoded by GJC1), and Panx was assessed in pulmonary arteries from Cx43+/− mice along with gene expression of various mediators known to play a role in the development of PAH: Tph, endothelial nitric oxide synthase (eNOS, encoded by NOS3), and bone morphogenetic receptor type II (BMPRII, encoded by BMPR2). Dysregulated bone morphogenetic protein (BMP) signaling is thought to be pivotal to the pathophysiology of PAH [27]
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