Endothelial senescence mediates hypoxia-induced vascular remodeling by modulating PDGFB expression

Area of Science:

• Cardiovascular Biology
• Cellular Senescence
• Pulmonary Hypertension Research

Background:

• Pulmonary hypertension (PH) is characterized by uncontrolled smooth muscle cell accumulation in pulmonary arterioles.
• Cellular senescence is implicated in aging and lung diseases, including PH, but its precise role in vascular remodeling remains unclear.
• Elevated senescence markers (p16INK4A, SA-β-gal) are observed in pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension (IPAH) patients.

Purpose of the Study:

• To investigate the mechanism by which cellular senescence controls vascular remodeling in PH.
• To elucidate the role of endothelial p16INK4A in hypoxia-induced vascular remodeling.
• To determine the impact of endothelial senescence on TWIST1-PDGFB signaling in PH.

Main Methods:

• Analysis of senescence markers in PAECs from IPAH patients and healthy individuals.
• Utilizing p16INK4A conditional knockout mice (p16iΔEC) to assess hypoxia-induced vascular remodeling.
• Transcriptomic analysis of IPAH patient lungs and hypoxia-treated mouse lung ECs.
• Investigating the effects of p16INK4A knockdown on gene expression and cell accumulation.
• Examining the role of exosomes derived from ECs in PASMC proliferation and migration.

Main Results:

• Hypoxia-induced αSMA-positive cell accumulation in pulmonary arteries was reduced in p16iΔEC mice.
• Transcriptomic data revealed altered senescence-related gene expression and interaction with TWIST1 in IPAH and hypoxia models.
• Knockdown of p16INK4A attenuated TWIST1 and PDGFB expression and suppressed αSMA-positive cell accumulation.
• Exosomes from hypoxia-treated ECs promoted PASMC proliferation and migration, an effect inhibited by exosomes from p16iΔEC mice.

Conclusions:

• Endothelial senescence, specifically via p16INK4A, modulates TWIST1-PDGFB signaling.
• This endothelial senescence-driven pathway controls vascular remodeling in pulmonary hypertension.
• Targeting endothelial senescence presents a potential therapeutic strategy for PH.