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Notch signaling regulates arterial vasoreactivity through opposing functions of Jagged1 and Dll4 in the vessel wall.
Functional interactions between endothelial cells (ECs) and smooth muscle cells (SMCs) in the arterial wall are necessary for controlling vasoreactivity that underlies vascular resistance and tone. Key signaling pathways converge on the phosphorylation of myosin light chain (P-MLC), the molecular signature of force production in SMCs, through coordinating the relative activities of myosin light chain kinase (MLCK) and myosin phosphatase (MP). Notch signaling in the vessel wall serves critical roles in arterial formation and maturation and has been implicated in arterial vasoregulation. In this report, we hypothesized that Notch signaling through ligands Jagged1 (in SMC) and Dll4 (in ECs) regulates vasoreactivity via homotypic (SMC-SMC) and heterotypic (EC-SMC) cell interactions. Using ligand induction assays, we demonstrated Jagged1 selectively induced smooth muscle MLCK gene expression and P-MLC content while inhibiting MP function (i.e. increased Ca2+ sensitization) in a ROCKII dependent manner. Likewise, selective deficiency of smooth muscle Jagged1 in mice resulted in MLCK and P-MLC loss, reduced Ca2+ sensitization, and impaired arterial force generation measured by myography. In contrast, smooth muscle Notch signaling triggered by Dll4 increased expression of myosin phosphatase targeting subunit-1 (MYPT1, the MP regulatory subunit) while arteries from endothelial Dll4 deficient mice featured reduced MYPT1 levels, enhanced force production and impaired relaxation independent of endothelial derived nitric oxide (NO) signaling. Taken together, this study identifies novel opposing vasoregulatory functions for ligand-specific Notch signaling in the vessel wall, underscoring instructional signaling between endothelial and smooth muscle cells and suggesting Notch signals might behave as a "rheostat" in arterial tone control.
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