Abstract
Vascular development is an orchestrated process of vessel formation from pre-existing vessels via sprouting and intussusceptive angiogenesis as well as vascular remodeling to generate the mature vasculature. Bone morphogenetic protein (BMP) signaling via intracellular SMAD1 and SMAD5 effectors regulates sprouting angiogenesis in the early mouse embryo, but its role in other processes of vascular development and in other vascular beds remains incompletely understood. Here, we investigate the function of SMAD1/5 during early postnatal retinal vascular development using inducible, endothelium-specific deletion of Smad1 and Smad5. We observe the formation of arterial-venous malformations in areas with high blood flow, and fewer and less functional tip cells at the angiogenic front. The vascular plexus region is remarkably hyperdense and this is associated with reduced vessel regression and aberrant vascular loop formation. Taken together, our results highlight important functions of SMAD1/5 during vessel formation and remodeling in the early postnatal retina.
Highlights
Bone morphogenetic protein (BMP) signaling is a major regulator of blood vessel formation and maturation
We previously demonstrated that a crosstalk between the intracellular BMP effectors SMAD1 and SMAD5 and Notch signaling is required for proper sprouting angiogenesis during mouse embryonic development [7]
Our study highlights endothelial SMAD1/5 as regulators of distinct blood vessel formation phases in the early postnatal mouse retina and their deletion results in massive vascular defects
Summary
Bone morphogenetic protein (BMP) signaling is a major regulator of blood vessel formation and maturation. Several studies have demonstrated distinct roles of BMP ligands, receptors, coreceptors and intracellular effectors in many steps of the angiogenic process [1,2,3,4,5,6]. The principal intracellular effectors of these BMP signaling components, SMAD1 and SMAD5, have so far not been associated with the development of vascular diseases, prompting further investigations into their role in vascular development and function. After the initial formation of blood vessels via vasculogenesis, vessels form from pre-existing ones via sprouting or intussusceptive angiogenesis. Subsequent to the formation of the early network via sprouting and intussusceptive angiogenesis, the vasculature undergoes remodeling processes, such as vessel regression, to generate the mature vasculature [10]
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