Hydrostatic Pressure Controls Angiogenesis Through Endothelial YAP1 During Lung Regeneration

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Cellular Mechanotransduction

Background:

• Unilateral pneumonectomy (PNX) triggers lung growth with increased pulmonary artery (PA) pressure.
• The mechanosensitive transcriptional co-activator yes-associated protein (YAP1) in endothelial cells (ECs) is vital for post-PNX angiogenesis.

Purpose of the Study:

• To determine if elevated PA pressure following PNX regulates angiogenesis via YAP1.
• To elucidate the role of YAP1 in ECs responding to mechanical stimuli during lung regeneration.

Main Methods:

• Applying hydrostatic pressure to human pulmonary arterial ECs (HPAECs) and analyzing YAP1, TEAD1, and Tie2 expression.
• Utilizing YAP1 siRNA and a YAP1S94A mutant to assess YAP1's function in ECs.
• Conducting gene enrichment analysis on post-PNX mouse lung ECs.
• Performing proteomics analysis on exosomes from post-PNX mouse lung ECs and assessing their pro-angiogenic effects in fibrin gels.

Main Results:

• Hydrostatic pressure increased YAP1, TEAD1, and Tie2 expression and stimulated EC DNA synthesis, migration, and sprouting, effects inhibited by YAP1 knockdown or YAP1S94A mutant.
• Gene enrichment analysis showed altered expression of ECM, cell adhesion, regeneration, and angiogenesis genes in post-PNX mouse lung ECs interacting with YAP1.
• Exosomes from post-PNX mouse lung ECs or pressurized ECs promoted host EC recruitment and blood vessel formation, an effect dependent on YAP1.

Conclusions:

• Elevated PA pressure following PNX stimulates angiogenesis through YAP1-mediated pathways.
• YAP1 plays a critical role in endothelial cell mechanotransduction, driving angiogenesis essential for lung regeneration.
• Exosomes derived from activated ECs contribute to vascular repair and regeneration post-PNX, mediated by YAP1.