Pericytes, mesenchymal stem cells and vascular calcification in chronic kidney disease (CKD). Is hedgehog signaling the missing link between endothelial injury and vascular sclerosis?

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Cardiovascular disease accounts for more than half of all deaths in patients with chronic kidney disease (CKD). Vascular calcification is an important contributor to this cardiovascular mortality. Recent studies suggest that pericytal mesenchymal stem cells (MSC) are major players in the vascular calcification process. The current study is based on the hypothesis that, in the case of endothelial dysfunction/damage as in CKD, altered endothelial-mesenchymal hedgehog (Hh) signaling leads to activation and recruitment of MSC from the vascular tube as the stem cell niche to support the regenerative processes by their paracrine and biosynthetic activity. In response to metabolic and inflammatory stress, they (mal)differentiate into osteoblasts. Using genetic and pharmacologic tools, we propose three specific aims to identify the functional roles of Hh signaling and pericytal MSC in the vessel wall during the process of vascular calcification: 1) We plan to characterize at cellular resolution the vascular expression patterns of the Hh pathway ligands, Ihh and Shh, Hh receptors Ptc-1 and Smo and the transcriptional effectors Gli 1-3 during vascular calcification in a mouse model of CKD. 2) We will test the hypothesis that pericytal MSC respond to injury-induced endothelial Hh signals by secreting paracrine factors, proliferation and differentiation towards a prosynthetic osteogenic phenotype leading to extracellular matrix densification, sclerosis and finally calcification. We will use genetic lineage tracing and primary pericyte/MSC culture to address these questions. 3) Finally, we will try to determine in vivo whether Hh pathway activation or inhibition leads to increased or reduced vascular sclerosis and calcification in CKD mice.