From niche to function: how endothelial cell interactions orchestrate muscle function in health and disease

Objetivo

Peripheral artery disease (PAD) is a common and debilitating condition affecting over 230 million people worldwide. While traditionally considered a macrovascular disease, many patients experience persistent muscle dysfunction even after successful revascularization. Recent evidence indicates that structural and functional pathology in skeletal muscle contribute to PAD pathophysiology, but underlying mechanisms remain poorly understood.

InterECt hypothesizes that dysfunctional crosstalk within the muscle microvascular niche drives muscle pathophysiology in PAD. We propose to systematically explore how heterogeneous and specialized endothelial cells (ECs) interact with other cells in their niche to maintain muscle homeostasis and to evaluate how altered interactions contribute to muscle dysfunction. Our preliminary data reveal that immunoregulatory EC subpopulations are dysfunctional in PAD patients and altered EC-macrophage interactions may contribute to disease progression.

Through three complementary aims, InterECt will: (1) provide detailed insight into the composition and transcriptional heterogeneity of the skeletal muscle vascular niche in health and PAD using human samples and several mouse models with single-cell transcriptomics and spatial technologies; (2) use novel genetic tools (uLIPSTIC and TAT-Cre systems) to decode functional cellular crosstalk within the vascular niche in vivo; and (3) employ mosaic gene perturbation using AAV-mediated CRISPR to mechanistically dissect how EC-niche crosstalk controls muscle homeostasis and repair.

By integrating human translational studies with cutting-edge mouse genetics and single-cell technologies, InterECt will deepen our understanding on muscle pathology in PAD beyond arterial obstruction, thereby identifying novel targets that restore muscle function by modulating vascular niche interactions.