Wednesday, April 23, 2025
4/23/2025
RSPO2-LGR4 signaling in atherosclerosis - PROJECT SUMMARY Recent investigations utilizing cell-lineage tracing, single-cell RNA-sequencing (scRNA-seq), and genomic approaches have revealed a crucial role of vascular smooth muscle cells (VSMCs) in atherosclerosis. These cells regulate the phenotype of other types of arterial cells via secreting various soluble factors, transform into lipid-laden foam cells, and undergo dedifferentiation into synthetic phenotype cells, contributing to the development of atherosclerosis. Additional studies identified an indispensable role of the lymphatic network in the removal of cholesterol and inflammatory cells/cytokines from the arterial wall, thereby inhibiting atherosclerosis. Moreover, surgical and genetic disruption of lymphatic drainage leads to aggravated atherosclerotic lesion formation. However, our knowledge of the endogenous factors and mechanisms regulating arterial lymphangiogenesis and VSMC phenotype remains limited. We have recently reported the elevated expression of a matricellular secretory protein R-spondin 2 (RSPO2) in human and murine atherosclerotic arteries, particularly in VSMCs, identified the anti-lymphangiogenic potential of RSPO2, and observed attenuated atherosclerosis and improved arterial lipid drainage with blockade of periadventitial Rspo2-induced signaling. Additional new data demonstrate increased LGR4 expression in atherosclerotic vascular tissue and reveal LGR4 as a predominant receptor for RSPO2 in lymphatic endothelial cells (LECs) and VSMCs. Besides, elevated RSPO2 expression is detected in neointimal VSMCs of injured carotid arteries in mice. However, the autocrine and paracrine roles of VSMC-secreted Rspo2 in regulating arterial lymphangiogenesis, VSMC phenotypic switch, and atherosclerosis development remain unknown. Based on these findings, our central hypothesis is that VSMC-derived Rspo2 via interacting with Lgr4 promotes atherosclerosis. In Aim 1, we will determine the functional role of VSMC Rspo2 in regulating arterial lymphangiogenesis, lymphatic function, and atherogenesis using in vitro studies and a novel SMC-specific Rspo2 knockout mouse model that we recently created. Aim 2 will focus on investigating the involvement of Lgr4 present in LECs in regulating arterial lymphangiogenesis and atherosclerosis development (progression and regression) using inducible LEC-restricted Lgr4-deficient mice. In Aim 3, we will explore the mechanisms responsible for the induction of RSPO2 levels in VSMCs and the contribution of RSPO2-LGR4 signaling in VSMC phenotypic modulation (scRNA-seq), neointima formation, and atherogenesis (in Lgr4-deficient mice) utilizing SMC-lineage tracing mice with Rspo2- or Lgr4-deficiency. The successful completion of these studies will provide novel insights into the mechanisms governing arterial lymphangiogenesis, VSMC phenotypic plasticity, and atherosclerosis development, and identify novel therapeutic targets for atherosclerosis. To ensure the success of the proposed studies, we have assembled a multidisciplinary team comprising a collaborator and consultants.
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