Connexin 43 Affects Pulmonary Artery Reactivity via Changes in Nitric Oxide Production and Influences Proliferative and Migratory Responses in Mouse Pulmonary Artery Fibroblasts

TL;DR

This study shows that Connexin 43 affects lung artery function and cell behavior in mice, with both protective and harmful effects.

Contribution

The study reveals a dual role of Cx43 in regulating fibroblast activity and vascular relaxation through nitric oxide signaling.

Findings

Cx43 inhibition reduces fibroblast proliferation under normoxia and hypoxia.

Reduced Cx43 compromises nitric oxide-dependent vascular relaxation.

Cx43 influences both proliferative and migratory responses in pulmonary artery fibroblasts.

Abstract

Pulmonary hypertension (PH) is a complex condition characterized by pulmonary artery constriction and vascular remodeling. Connexin 43 (Cx43), involved in cellular communication, may play a role in PH development. Cx43 heterozygous (Cx43+/−) mice show partial protection against hypoxia-induced pulmonary remodeling, with prior research highlighting its role in rat pulmonary artery fibroblast (PAF) proliferation and migration. However, inhibiting Cx43 may compromise nitric oxide (NO)-mediated vascular relaxation. This study evaluated the effects of Cx43 on mouse PAF (MPAF) proliferation, migration, NO-dependent and independent pulmonary vascular relaxation, and NO synthesis. Proliferation and migration were assessed in Cx43+/− MPAFs under normoxic and hypoxic conditions. Vascular responses were analyzed in intra-lobar pulmonary artery rings with acetylcholine (ACh), SNAP, and U46619, while NO production was measured in lung tissue. Both genetic knockdown and pharmacological inhibition of Cx43 significantly reduced serum-induced proliferation but not migration under normoxia, while 37,43Gap27 inhibited hypoxia-induced proliferation and migration. The effects of genetic knockdown and pharmacological inhibition of Cx43 on vascular reactivity were also investigated. NO-dependent and independent relaxations and NO production were reduced in Cx43+/− mice by 37,43Gap27. In conclusion, while Cx43 inhibition may protect against PAF proliferation and migration, it could also impair pulmonary vascular relaxation, at least in part through a reduction in NO signaling. Further studies are needed to fully understand the mechanisms by which Cx43 influences NO signaling.

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