Pivotal role of VEGFR2 in type H endothelial cells in endochondral ossification during bone growth and regeneration

Abstract

Encochondral ossification process, which is involved in the growth and regeneration of bone tissue, is known to progress in coupling of angiogenesis and osteogenesis. Key ligands and receptors that regulate coupling of angiogenesis-osteogenesis and control proper bone growth and regeneration are poorly understood. In present study, I show that VEGFR2 signaling in type H endothelial cells (ECs) mainly drives the coupling of angiogenesis-osteogenesis by upregulating Dll4, Noggin, and MMP9 during longitudinal bone growth. In comparison, VEGFR3 and Tie2 signaling have negligible roles in type H ECs and do not alter the effects of VEGFR2 signaling in the coupling of angiogenesis-osteogenesis during longitudinal bone growth. Moreover, during bone regeneration after fracture, Type H ECs reappear while distinct levels of angiogenic receptors were shown. Endothelial VEGFR2 also plays key roles in the endochondral ossification during bone regeneration. Similarly, VEGFR2 signaling in type H ECs positively regulates the activity of Notch signaling and the synthesis of Noggin and MMP9 during bone regeneration. Together, I show the pivotal roles of VEGFR2 in type H ECs in endochondral ossification during bone growth and regeneration.