Mechanosensitive PPAP2B Regulates Endothelial Responses to Atherorelevant Hemodynamic Forces

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Biophysics

Background:

• Genome-wide association studies implicate PhosPhatidic Acid Phosphatase type 2B (PPAP2B) in coronary artery disease (CAD).
• The role of PPAP2B in endothelial mechanotransduction and response to hemodynamic forces remains unclear.
• Understanding PPAP2B's function is vital for elucidating atherosclerosis pathogenesis.

Purpose of the Study:

• To determine the critical role of PPAP2B in endothelial responses to hemodynamic forces.
• To investigate the regulatory mechanisms of PPAP2B expression in the endothelium.
• To link PPAP2B's function to vascular integrity and inflammation under atherosusceptible conditions.

Main Methods:

• In vivo studies in mouse and swine models exposed to altered blood flow.
• In vitro studies using human aortic endothelial cells under controlled flow conditions.
• Analysis of microRNA and transcription factor involvement (miR-92a, KLF2) and receptor signaling (LPA1/2).

Main Results:

• PPAP2B expression was reduced in vivo and in vitro under disturbed or low shear stress conditions mimicking atherosclerosis.
• Flow-sensitive miR-92a and KLF2 were identified as regulators of endothelial PPAP2B.
• PPAP2B deficiency impaired atheroprotective flow responses, leading to increased vascular permeability, which was rescued by inhibiting lysophosphatidic acid receptors.

Conclusions:

• Endothelial PPAP2B expression is dynamically modulated by atherorelevant blood flow via miR-92a and KLF2.
• Mechanosensitive PPAP2B is essential for maintaining endothelial anti-inflammatory phenotype and vascular integrity under protective flow.
• PPAP2B plays a critical role in vascular response to hemodynamics, influencing CAD risk.