The long-term goal of this project is to identify cellular and molecular mechanisms that regulate the development and function of the tunica adventitia, an important but poorly understood layer of artery wall. We recently discovered a sonic hedgehog (Shh) signaling domain in developing conduit arteries and veins that is localized exclusively to the adventitia and contains resident Sca1+ progenitor cells (AdvSca1). In vertebrates, Hh proteins are morphogens that activate smoothened (SMO)-dependent signaling pathways to pattern connective tissue, control arterial-venous identity, and direct growth and survival functions for lineage-specific stem/progenitor cells. In the vascular system, the adventitia plays important roles in artery wall homeostasis and disease. The adventitia contains vasa vasorum microvessels that are key conduits for leukocyte trafficking into and out of atherosclerotic lesions. In addition, vessel wall remodeling, arterial tone and compliance, and perivascular adipose tissue are all critically dependent on the adventitia. Most forms of arterial injury evoke rapid and robust adventitial reactions suggesting that cellular and molecular pathways that sense and respond to injury are intrinsic functions of adventitial cells. Our published and preliminary data identify a resident Shh- dependent progenitor cell population that is mobilized in response to multiple forms of vascular injury. Our preliminary studies using ShhEGFP/+ reporter mice suggest that the primary producers of Shh in the adventitia are AdvSca1 cells themselves. By contrast, Gli1lacZ/+, Ptc1lacZ/+, and Ptc2lacZ/+ reporter mice indicate that the majority of Shh-responsive cells in the adventitia are CD68+, F4/80+, and Csf1R+ resident macrophage-like cells (AdvRM). AdvRM cells are clustered in close proximity to, or in direct contact with, AdvSca1 cells in the inner adventitia. These results raise the novel possibility of a progenitor cell niche in the inner adventitia that is formed and maintained by reciprocal signaling interactions between AdvSca1 progenitor cells and AdvRMs. We propose that cells within the adventitial progenitor niche function at the media-adventitia interface to initiate compensatory wall remodeling and repair responses via paracrine signaling pathways in the vessel wall. To test this novel hypothesis, we will emphasize whole animal experiments and genetic fate mapping approaches in vivo. The results of this project will change our current understanding of the roles of the adventitia in development, homeostasis and disease of the artery wall.
The research proposed in this application seeks to identify new targets for regenerative therapies directed to the artery wall. We discovered that embryonic morphogen signaling pathways support resident vascular stem/progenitor cells in the outer layer of artery wall called the tunica adventitia. Our studies will test the functions of these cells in artery wall development, repair and disease. We believe new therapeutic targets will emerge from further study of the adventitial layer of the artery wall.