Abstract 20489: Arterial Vasoregulation by Notch Signaling

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Notch signaling is an evolutionarily conserved molecular pathway required for proper cardiovascular development and function. In arterial vasculature, membrane-bound Notch ligands and receptors act in trans to mediate cell-specific activities including cell fate decisions, differentiation, and proliferation. We previously reported a role for Notch signaling in vascular smooth muscle as a novel regulator of arterial contractility in part through targeting myosin light chain kinase (MLCK), which catalyzes myosin light chain phosphorylation (p-MLC) required for actin-myosin cross-bridging and force generation. We sought to identify the Notch ligands responsible for transducing the contractile phenotype. Arterial segments from mice deficient in either Jagged1 or Dll4 ligand were subjected to wire-mounted myography and biochemical assays to measure force production at the tissue and molecular levels, respectively. We determined Jagged1 loss blunted constrictor-induced force associated with reduced MLCK content. In contrast, Dll4 deficiency enhanced force in parallel with reduction in MYPT1, the myosin binding subunit of myosin phosphatase responsible for dephosphorylating p-MLC. Taken together, these observations suggest novel Notch ligand-specific vasoregulatory functions that conceptually parallel the antagonistic roles of endothelial Jagged1 and Dll4 in angiogenesis. Furthermore, Dll4 is predominantly expressed within arterial endothelium implicating heterotypic interactions between Dll4-bearing endothelial cells and smooth muscle Notch receptors might underlie a functionally relevant endothelial-dependent vasoregulatory pathway. We conclude ligand-dependent Notch signaling in the vascular wall might function as a local rheostat for arterial tone through regulatory control of p-MLC content and activity. Ongoing investigation of ligand-specific triggering and cellular interplay will be important for Notch-targeted pharmacological strategies aimed at therapeutic manipulation of peripheral vasoreactivity in vascular disease.

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