When platelets are under pressure: an angiotensin II-TGF-β axis in hypertensive patients leads to receptor PAR4 overexpression

Abstract

Angiotensin II-TGF-β1-Smad2 signalling promotes PAR4 overexpression and platelet priming in hypertension. The schematic depicts the proposed mechanism by which an angiotensin II-high hypertensive phenotype drives megakaryocyte reprogramming and platelet hyperreactivity. In normosensitive individuals and in hypertensive patients without increased angiotensin II signalling, TGF-β1, Smad2 activation, and platelet PAR4 expression remain unchanged, resulting in quiescent platelets. In contrast, increased angiotensin II signalling promotes TGF-β1/Smad2 activation in megakaryocytes, leading to increased PAR4 expression in newly generated platelets. PAR4-high platelets display increased platelet activation markers and are associated with enhanced thrombotic risk. Valsartan, through angiotensin II type 1 receptor blockade, attenuates this pathway and may reduce PAR4-dependent platelet activation in this specific hypertensive phenotype.