Coronary heart disease is the leading cause of death worldwide, yet coronary artery (CA) development and regeneration remains incompletely understood. Artery development is guided by both genetic and mechanical cues, the latter of which involves hemodynamic forces that function to shape the hierarchal organization of vascular beds. Mechanical signals are particularly important for CA development since their differentiation is only induced after the unperfused coronary plexus attaches to the aorta and begins to receive blood flow. Our long-term goal is to understand how initiation of coronary blood flow is translated into developmental signals that trigger CA differentiation and stimulate their subsequent maturation and stabilization. We recently discovered that Dach1, a transcription factor in the Drosophila retinal determination gene network (RDGN), is expressed in developing CAs, but is downregulated by high, laminar shear stress once the vessels mature. CAs in Dach1 knockout mice are small with frequent structural abnormalities including some loss of hierarchal structure. Furthermore, Dach1 depletion in vitro decreases the proliferation and migration of coronary endothelial cells. The goal of this project is to identify the mechanisms through which Dach1 supports CA development and whether its flow-induced downregulation is necessary for maturation and/or stabilization. We hypothesize that Dach1 interacts with other RDGN members to regulate the transcription of genes essential for proper CA growth, and that this activity must be decreased during vessel maturation/stabilization due to its inhibition of BMP/SMAD- induced vascular quiescence. These hypotheses will be tested in three Aims. We will (1) identify how Dach1 influences gene transcription, whether RDGN members act as its partners, and how these interactions modulate endothelial cell behavior during CA development, (2) investigate the function of high shear stress mediated Dach1 downregulation during artery maturation, and (3) test whether Dach1 interacts with BMP/SMAD to regulate artery size. These studies will delineate how Dach1/RDGN transcriptional complexes direct arteriogenesis. They will also provide insight into the mechanisms by which hemodynamic forces regulate transcriptional programs to shape the hierarchal organization of the mature vascular tree. Knowledge of these mechanisms could be utilized stimulate the growth of existing or new arteries during disease.
This proposal investigates how RDGN transcription factor complexes stimulate coronary artery development. Coronary artery disease is the leading cause of death worldwide and represents a significant healthcare burden for tens of millions who manage its symptoms medically or with surgical interventions. Our findings should identify pathways that could be utilized to generate new coronary arteries in disease settings.
