Cx43 Regulates Nicotine-Induced Proliferation and Migration of Distal Pulmonary Artery Smooth Muscle Cells by the ERK1/2 Signaling Pathway

Pulmonary hypertension is a progressive disease associated with remodeling of the pulmonary vasculature. Excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) play important roles in nicotine-induced vascular injury. Connexin 43 (Cx43) is involved in intracellular communication and regulation of the pulmonary vasculature. However, the role of Cx43 and the potential mechanisms in PASMCs proliferation and migration induced by nicotine remains not very clear. In this study, we used both in vitro and in vivo models to explore the crucial role of Cx43 in pulmonary artery remodeling in nicotine treatment Tagln-Cre; Cx43^+/+ and Cx43 heterozygous (Tagln-Cre; Cx43^flox/+) or Cx43 Homozygous (Tagln-Cre; Cx43^flox/flox) deletion mice, and further explore the mechanism. We found that nicotine exposure led to modifications in the morphology and ultrastructure of pulmonary arteries in Tagln-Cre; Cx43^+/+ mice. Nicotine increased the Cx43 expression of pulmonary arteries and promoted the proliferation and migration of PASMCs of Tagln-Cre; Cx43^+/+ mice in a concentration-dependent manner by promoting ERK1/2 phosphorylation. Compared with the Tagln-Cre; Cx43^+/+ mice, the Tagln-Cre; Cx43^flox/+ mice were protected against increased ERK1/2 phosphorylation induced by nicotine. These results demonstrated that the downregulation of Cx43 reduced nicotine-induced proliferation and migration of distal PASMCs by inhibiting ERK1/2 phosphorylation.