Nestin represents a potential marker of pulmonary vascular remodeling in pulmonary arterial hypertension associated with congenital heart disease

J Mol Cell Cardiol. 2020 Dec:149:41-53. doi: 10.1016/j.yjmcc.2020.09.005. Epub 2020 Sep 18.

Abstract

Objective: Reportedly, nestin was re-expressed in proliferative synthetic-type pulmonary artery smooth muscle cells (PASMCs) and obligatory for PASMC proliferation in pulmonary arterial hypertension (PAH). Accordingly, nestin is increased in pulmonary vascular lesions of congenital heart disease (CHD)-associated PAH patients. We tested the hypothesis whether nestin was re-expressed in proliferative synthetic-type PASMCs and associated with pulmonary vascular remodeling in CHD-PAH.

Materials and methods: Nestin expression was tested using lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV) shunt-induced PAH rats, human PASMCs (HPASMCs), and pulmonary artery endothelial cells (PAECs) and PASMCs from MCT-AV-induced PAH rats. The role and possible mechanism of nestin on HPASMC proliferation, apoptosis, cell cycle and migration were investigated by assays of CCK-8, EdU, TUNEL, flow cytometry, transwell chamber and immunoblotting assays.

Results: Nestin was solely expressed in proliferative synthetic-type PASMCs, but rarely detected in PAECs. Nestin was barely detected in normal pulmonary arterioles and occlusive pulmonary vascular lesions. Its expression was robustly increased in developing pulmonary vasculature, but returned to normal levels at the late stage of pulmonary vascular remodeling in lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats. Besides, nestin peaks were consistent with the histological features in lung tissues of MCT-AV-induced PAH rats. Moreover, nestin overexpression effectively promoted HPASMC phenotypic transformation, proliferation, apoptosis resistance and migration via enhancing Wnt/β-catenin activation.

Conclusions: These data indicated that nestin was re-expressed in proliferative synthetic-type PASMCs and might represent a potential marker of pulmonary vascular remodeling in CHD-PAH.

Keywords: Congenital heart disease; Nestin; Pulmonary arterial hypertension; Pulmonary arterial smooth muscle cell; Wnt/β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Biomarkers / metabolism
  • Child
  • Child, Preschool
  • Endothelial Cells / metabolism
  • Female
  • Heart Defects, Congenital / complications
  • Heart Defects, Congenital / metabolism*
  • Heart Defects, Congenital / physiopathology*
  • Humans
  • Lung / physiopathology*
  • Male
  • Middle Aged
  • Monocrotaline
  • Myocytes, Smooth Muscle / metabolism
  • Nestin / metabolism*
  • Phenotype
  • Proliferating Cell Nuclear Antigen / metabolism
  • Pulmonary Arterial Hypertension / complications
  • Pulmonary Arterial Hypertension / metabolism*
  • Pulmonary Arterial Hypertension / physiopathology*
  • Pulmonary Artery / pathology
  • Rats, Sprague-Dawley
  • Time Factors
  • Vascular Remodeling*
  • Wnt Signaling Pathway
  • Young Adult

Substances

  • Biomarkers
  • Nestin
  • Proliferating Cell Nuclear Antigen
  • Monocrotaline