Type H vessel/platelet-derived growth factor receptor β+ perivascular cell disintegration is involved in vascular injury and bone loss in radiation-induced bone damage

Collapse of the microvascular system is a prerequisite for radiation-induced bone loss. Since type H vessels, a specific bone vessel subtype surrounded by platelet-derived growth factor receptor β⁺ (PDGFRβ⁺ ) perivascular cells (PVCs), has been recently identified to couple angiogenesis and osteogenesis, we hypothesize that type H vessel injury initiates PDGFRβ⁺ PVC dysfunction, which contributes to the abnormal angiogenesis and osteogenesis after irradiation. In this study, we found that radiation led to the decrease of both type H endothelial cell (EC) and PDGFRβ⁺ PVC numbers. Remarkably, results from lineage tracing showed that PDGFRβ⁺ PVCs detached from microvessels and converted the lineage commitment from osteoblasts to adipocytes, leading to vascular injury and bone loss after irradiation. These phenotype transitions above were further verified to be associated with the decrease in hypoxia-inducible factor-1α (HIF-1α)/PDGF-BB/PDGFRβ signalling between type H ECs and PDGFRβ⁺ PVCs. Pharmacological blockade of HIF-1α/PDGF-BB/PDGFRβ signalling induced a phenotype similar to radiation-induced bone damage, while the rescue of this signalling significantly alleviated radiation-induced bone injury. Our findings show that the decrease in HIF-1α/PDGF-BB/PDGFRβ signalling between type H ECs and PDGFRβ⁺ PVCs after irradiation affects the homeostasis of EC-PVC coupling and plays a part in vascular damage and bone loss, which has broad implications for effective translational therapies.