Cardiovascular disease (CVD), such as athersoclerosis, arteriosclerosis and instentrestenosis leading to a heart attack or stroke is the number one cause of death in the EU and Ireland. Structural remodelling associated with CVD occurs due to the accumulation of vascular smooth muscle cells (vSMC) within the vessel wall. However the source and origin of these cells remains controversial. Emerging evidence now suggests that (i) resident vascular stem cells differentiate to vSMC and contribute to structural remodelling (ii) there exists an increased vascular disease susceptibility within specific embryological neuroectoderm [NE] regions of the vesel wall, as compared to presomitic mesdoerm [PM]. This raises the important question as to whether resident vascular stem cells from within these NE regions are functionally distinct to PM regions based on their response to morphogenic cues? Transient activity of the morphogen sonic hedgehog (SHh) is known to promote stem cell self-renewal, whereas continuous activation leads to stem cell growth and differentiation during progression of many diseases. Importantly, GWAS studies have recently highlighted Hedgehog (Hh) loci as predictive of increased CVD susceptibility in humans. We have recently shown that local perivascular inhibition of Hh signaling within NE derived vessels attenuates medial intimal thickening and structural remodelling. This application will examine the putative role of SHh in controlling selfrenewal and/or transition to SMC of resident vascular stem cells derived from NE and PM. Using Sca1+ adventitial progenitor cells (APCs) and Nestin+ multipotent vascular stem cells (MVSCs) isolated from both the NE-derived ascending aorta and the PM-derived descending thoracic aorta, in conjunction with human iPS derived stem cells to chemically generate NE and PM intermediates and vSMC derivatives, the effects of Hh signaling on stem cell renewal and differentiation to vSMC will be assessed in vitro and validated in vivo using cell fate mapping following vascular
injury.
