Vascular endothelial S1pr1 ameliorates adverse cardiac remodeling via stimulating reparative macrophage proliferation after myocardial infarction

AIMS: Endothelial cell (EC) homeostasis plays an important role in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodeling after myocardial infarction (MI). It has been shown that the sphingosine 1-phospahte receptor 1 (S1pr1) was highly expressed in ECs and played an important role in maintaining endothelial functions. We thus hypothesized that the endothelial S1pr1 might be involved in post-MI cardiac remodeling. METHODS AND RESULTS: Our study showed that the specific loss of endothelial S1pr1 exacerbated post-MI cardiac remodeling and worsened cardiac dysfunction. We found that the loss of endothelial S1pr1 significantly reduced Ly6clow macrophage accumulation, which is critical for the resolution of inflammation and cardiac healing following MI. The reduced reparative macrophages in post-MI myocardium contributed to the detrimental effects of endothelial S1pr1 deficiency on post-MI cardiac remodeling. Further investigations showed that the loss of endothelial S1pr1 reduced Ly6clow macrophage proliferation, while the pharmacological activation of S1pr1 enhanced Ly6clow macrophage proliferation and thereby ameliorated cardiac remodeling after MI. A mechanism study showed that S1P/S1pr1 activated the ERK signaling pathway and enhanced colony stimulating factor 1 (CSF1) expression, which promoted Ly6clow macrophage proliferation in a cell-contact manner. The blockade of CSF1 signaling reversed the enhancing effect of S1pr1 activation on Ly6clow macrophage proliferation and worsened post-MI cardiac remodeling. CONCLUSIONS: This study reveals that cardiac microvascular endothelium promotes reparative macrophage proliferation in injured hearts via the S1P/S1PR1/ERK/CSF1 pathway and thus ameliorates post-MI adverse cardiac remodeling. TRANSLATIONAL PERSPECTIVE: This study highlights the importance of the local vascular microenvironment in orchestrating tissue inflammation and remodeling by regulating self-replenishment of tissue local reparative macrophages. Our studies demonstrate that ECs tightly control post-MI reparative Mo/Mvarphi proliferation via the S1P/S1PR1/CSF1 pathway in a cell-contact manner. This implies that a feasible modulation of vascular niche signals might provide a promising target to resolve excessive inflammation and to ameliorate adverse cardiac remodeling after MI.