TGF β1 Drives Integrin Dependent Pericyte Migration and Microvascular Destabilization In Fibrotic Disease

Am J Pathol. 2024 Mar 26:S0002-9440(24)00118-4. doi: 10.1016/j.ajpath.2024.02.021. Online ahead of print.ABSTRACTInteractions between endothelial cells (EC) and mural pericytes (PC) are critical to maintaining the stability and function of the microvascular wall. Abnormal interactions between these two cell types are a hallmark of progressive fibrotic diseases, such as systemic sclerosis (SSc, scleroderma). However, the role that PCs play in signaling microvascular dysfunction remains underexplored. It is hypothesized that integrin-matrix interactions contribute to PC migration from the vascular wall and conversion into interstitial myofibroblasts. Using pro-inflammatory TNF alpha (TNFα) or fibrotic growth factor TGF beta-1 (TGFβ1), human PC inflammatory and fibrotic phenotypes were evaluated by assessing their migration, matrix deposition, integrin expression, and subsequent effects on endothelial dysfunction. Both TNFα and TGFβ1 treatment altered integrin expression and matrix protein deposition, but only fibrotic TGFβ1 drove PC migration in an integrin-dependent manner. In addition, integrin-dependent PC migration was correlated to changes in EC angiopoietin-2 levels, a marker of vascular instability. Finally, there was evidence of changes in vascular stability corresponding to disease state in human SSc skin. The work presented demonstrates that TNFα and TGFβ1 induce changes in PC integrin expression and matrix deposition that facilitate migration and reduce vascul...

Source: Am J Pathol - March 28, 2024 Category: Pathology Authors: Amanda S Pellowe Michelle J Wu Tae-Yun Kang Tracy D Chung Adrian Ledesma-Mendoza Erica Herzog Andre Levchenko Ian Odell John Varga Anjelica L Gonzalez Source Type: research