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Project A01

Organ-specific specialization of angiocrine signaling

Blood vessels provide a versatile and adaptable transport system, but recent work has established that cells of the vascular network are also a source of molecular cues controlling growth and patterning processes in the surrounding tissue. A striking example of organ-specific functional specialization of blood vessels is the skeletal system where a subset of capillary endothelial cells (ECs) controls osteoprogenitor cell behavior and thereby bone formation during development, adult homeostasis and aging. By contrast, little is known about regulation of bone-resorbing osteoclasts by the local vasculature. Based on preliminary results and because of the great importance of osteoclasts in health and disease, we are investigating how endothelial cells control bone resorption. We are focusing on the role of sphingosine-1 phosphate (S1P), which is a bioactive sphingolipid signaling molecule that regulates functions such as vascular tone, endothelial junction integrity and angiogenesis. S1P interacts with cell surface G protein-coupled receptors termed S1PR1 to 5, of which S1PR1 to 3 are expressed in the vasculature. Inactivation of the S1pr1 gene in mice leads to embryonic lethality due to massive hemorrhaging caused by defective mural cell recruitment and EC hyperproliferation. We are using inducible and cell type-specific gene inactivation approaches together with scRNA-seq and in vitro approaches to characterize the function of the S1PR1 receptor and its downstream effectors in bone endothelium. 

Image A1 Adams.png

Section through postnatal femur showing vATPase+ osteoclasts (green) in close proximitity to Endomucin+ (red) endothelium. Nuclei are labeled by DAPI (blue).

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