BMP-SMAD1/5 Signaling Is Required For Adequate Coupling Of Angiogenesis And Osteogenesis In Long Bones

Lang, Annemarie [Universitätsmedizin Berlin] Benn, Andreas [KU Leuven] Damerau, Alexandra [Universitätsmedizin Berlin] Boerckel, Joel D. [University of Pennsylvania] Kerckhofs, Greet [UCL] Zwijsen, An [KU Leuven]

The bone vasculature is essential for skeletal development, homeostasis, and regeneration. In long bones, specific capillary subtypes couple angiogenesis to osteogenesis, especially at the growth plate (metaphysis) and endosteum. These metaphyseal and endosteal vessels, termed “type H,” express high levels of CD31 and endomucin (CD31hiEmcnhi), show a columnar structure and are closely related to Osterix (Osx)- and Runt-related transcription factor 2 (Runx2)-expressing osteoblasts and their progenitors [1]. Sinusoidal vessels with low expression of CD31 and Emcn (CD31lowEmcnlow, type L vessels) are mainly found in the diaphysis/bone marrow cavity [1]. The crosstalk between endothelial cells (ECs) of type H vessels and bone-related cells is characterized by osteogenesis-promoting factors provided by ECs and angiogenic mediators secreted by osteoblast-lineage cells. Bone morphogenetic proteins (BMP) are major regulators of vessel formation, however their role within angiogenic and osteogenic coupling and in particular, the involvement of BMP-related intracellular effectors SMAD1 and SMAD5 (SMAD1/5) is unclear. Previously, we demonstrated that during mouse embryonic development, the synergy of Notch and SMAD1/5 is responsible for the balanced selection of tip and stalk cells in vascular sprouting [2]. Furthermore, we reported that endothelium-specific deletion of SMAD1/5 during early postnatal retinal angiogenesis resulted in arteriovenous malformations, a reduced number of tip cells and a hyperdensity in the vascular plexus [3]. Therefore, we hypothesized that functional EC-specific SMAD1/5 signaling is required for (i) formation and maturation of long bone vasculature and (ii) coupling of osteogenesis and angiogenesis, specifically of type H vessel formation in the metaphysis.