Introduction. Previously, we reported that mesenchymal activation of endothelial cells (ECs) drives cardiac fibrosis and failure in an angiocrine manner by secreting extracellular matrix and paracrine activation of fibroblasts. Whether pericytes (PCs), which ensure vascular integrity in a tight interplay with ECs, contribute to cardiac failure, remains unknown.
Objective. Aim of the study was to investigate the impact of pericyte activation on cardiac remodeling and failure following pressure overload.
Methods & Results. In a murine model of fibrotic remodeling by endothelial-to-mesenchymal activation (EndoMA) due to Cdh5-driven overexpression of Sox9 in endothelial cells, we found activation of a specific cluster of stressed pericytes with single-cell sequencing. As EndoMA is a main feature of cardiac pressure overload, we subjected mice to transverse aortic constriction (TAC) in order to investigate the role of PCs in this context. Following two weeks of TAC, we detected an increase in capillary density in line with enlargement of cardiomyocyte cross-sectional area. Interestingly, pericyte numbers increased in line with vessel number, keeping a constant PC—capillary ratio. As we identified Sox9 expression as marker in stressed PCs, we overexpressed Sox9 (Sox9OE) specifically in PCs utilizing the Pdgfrb-, or Cspg4-Cre driver. Both transgenes displayed onsets of cardiac failure after 3 months of overexpression, but surprisingly in the absence of cardiac fibrosis. Bulk RNA sequencing of isolated PCs revealed induction of inflammatory processes, which we verified with immunofluorescence by increased occurrence of CD45+ cells in cardiac cross-sections. Additionally, we observed increased vascular leakiness indicating reduced vessel integrity in both Pdgfrb-Sox9OE, and Cspg4-Sox9OE mice. With the identification of pericyte SOX9 as maladaptive driver of pericyte activation, we selectively deleted Sox9 in PCs (Sox9KO) and applied TAC. Strikingly, both Pdgfrb-Sox9KO, and Cspg4-Sox9KO mice showed maintained cardiac function, reduced vascular leakiness, and reduced number of inflammatory cells in the myocardium vs. TAC-operated wildtype littermates, while cardiac fibrosis was not mitigated.
Conclusions. Stress activation of cardiac pericytes induces a pro-inflammatory milieu after pressure overload. While they seem to not directly influence the degree of fibrosis, stressed PCs drive cardiac dysfunction by recruiting immune cells and impairing barrier function in a SOX9-dependent manner. Hence, pericyte stress responses might be a promising therapeutic target for cardiac disease.
