The vascular smooth muscle cell (VSMC) provides dynamic regulation of contractile tone during homeostasis, and is often dysfunctional in diseases involving vascular obstruction and hyper-proliferation of the vessel wall. VSMC modify their gene expression and contractile proteins in response to a variety of external stimuli, particularly during disease progression. The Notch signaling pathway is critical for proper cardiovascular development and is implicated in the pathogenesis of vascular disease. Human mutations in the JAGGED1, NOTCH2, or NOTCH3 genes lead to syndromes with cardiovascular structural defects and susceptibility to stroke. In addition, dysfunction of the Notch pathway is associated with vascular obstructive disease, cerebral vascular disorders, angiogenesis, arteriovenous malformations, and vasculitis. Despite the high significance of this pathway to human vascular disease, there is limited understanding of signaling mechanisms mediated by distinct Notch ligands and their corresponding receptors. Because components of the Notch pathway are therapeutic targets in cardiovascular disease and cancer, it is critical to clarify these signaling pathways. Our studies previously defined an important role for Jagged1/Notch signaling in promoting VSMC differentiation and suppressing proliferation. Part of this mechanism is via the transcriptional activation of miR143/145, which are important for VSMC maturation and function. In addition to Jagged1, a second Notch ligand, Dll1 is also produced during vasculogenesis and remodeling in response to vascular injury. Studies with human primary cells showed that Jagged1 and Dll1 activate distinct pathways consistent with Jagged1 regulating early commitment and differentiation of VSMC, and Dll1 promoting late maturation. These activities correlate with inverse regulation of miR143/145. We propose that the selective ligand effects are mediated through differential transcriptional complex assembly and gene regulation, leading to ligand-specific protein signatures. In addition, we discovered a novel function of Jagged1 signaling via Notch2 to regulate p27kip1 and suppress VSMC proliferation. Thus, the coordinated activities of Jagged1 and Dll1 regulate all phases of the VSMC life cycle from embryonic development to re-establishment of homeostasis following vascular injury.
The aims of this project are to: 1) Elucidate Jagged1- and Dll1-induced differential pathways and functional outcomes on VSMC recruitment and differentiation, 2) Discover novel components of differential Notch-mediated Jagged1- and Dll1-induced transcriptional complexes and their impact on gene expression and protein signatures, and 3) Identify mechanisms by which Jagged1 suppresses VSMC proliferation to maintain the contractile phenotype. These studies will provide novel insight into molecular signaling of the Notch pathway, which is a potential therapeutic target for the treatment of cardiovascular diseases.
Smooth muscle cells in the vessel wall are responsible for maintaining vascular tone and blood pressure, and their dysfunction can cause disease. Many cardiovascular diseases are associated with the narrowing of blood vessels, and this project will study smooth muscle cell signaling that can lead to vascular obstructive conditions including coronary artery disease, a major cause of mortality in the US population.
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