Novel PKA‐mediated mechanisms of microvascular endothelial barrier enhancement

• DOI: 10.1096/fasebj.31.1_supplement.1074.3
• Publication Date: 2023-11-26T17:16:59Z
• Authors: Robert Karoly Batori; Sanjiv Kumar; Mary Shaw; Zsuzsanna Bordan; Boris Gorshkov; Anita Kovacs‐Kasa; David Fulton; Alexander Verin
• Keywords: Myosin-light-chain phosphatase; Barrier function

Acute lung injury (ALI) is devastating disorder with an unacceptably high level of mortality. The pharmacological treatment ALI relies on supportive care and control initiating causes. Therefore, novel therapies are urgently needed to improve clinical outcomes. Endothelial cells (EC) form a semi‐permeable barrier between the interior space blood vessels underlying tissues. characterized by significant pulmonary inflammatory response resulting in protein‐rich edema due loss endothelial integrity. mechanisms that govern increased EC permeability under intense investigation, however, processes determining preservation/restoration function remain poorly understood. Our group has previously shown extracellular purines, ATP adenosine able preserve vascular murine model LPS‐induced enhance human artery (HPAEC) via activation myosin light chain (MLC) phosphatase (MLCP). MLCP may involve PKA‐dependent phosphorylation targeting subunit 1 (MYPT1) at S695, which activate directly or indirectly preventing its Rho kinase‐mediated subsequent T696 residue, direct link MLCP, PKA purine‐induced enhancement was not established. new data demonstrated stable analog, ATPγS, strengthen microvascular (HLMVEC). In contrast ATP, this effect accompanied but involved decrease MLC20 suggesting involvement MLCP. Surprisingly, adenosine, ATPγS‐induced does acompanied increase cAMP existance unconventional cAMP‐independent activation. Further, strengthening EPAC1, dependent upon non‐receptor type 11 tyrosine‐phosphatase (PTPN11, also known as Shp2) AKAP2 (PKA anchoring protein 2) expression. Furher, we can interact MYPT1 depletion restored reduced ATPγS treatment. Collectively, our suggest ATPγS‐, adenosine‐induced requires coordinated Shp2‐mediated then guided dephosphorylate MLC. Support Funding Information Supported HL101902