TGF-β signaling in endothelial cells, but not neuroepithelial cells, is essential for cerebral vascular development

The various organs of the body harbor blood vessel networks that display unique structural and functional features; however, the mechanisms that control organ-specific vascular development and physiology remain mostly unknown. In the developing mouse brain, αvβ8 integrin-mediated TGF-β activation and signaling is essential for normal blood vessel growth and sprouting. Whether integrins activate TGF-β signaling pathways in vascular endothelial cells (ECs), neural cells, or both, has yet to be determined. Here, we have generated and characterized mice in which TGF-β receptors are specifically deleted in neuroepithelial cells via Nestin-Cre, or in ECs via a novel Cre transgenic strain (Alk1(GFPCre)) in which Cre is expressed under control of the endogenous activin receptor-like kinase 1 (Alk1) promoter. We report that deletion of Tgfbr2 in the neuroepithelium does not impact brain vascular development. In contrast, selective deletion of the Tgfbr2 or Alk5 genes in ECs result in embryonic lethality because of brain-specific vascular pathologies, including blood vessel morphogenesis and intracerebral hemorrhage. These data reveal for the first time that αvβ8 integrin-activated TGF-βs regulate angiogenesis in the developing brain via paracrine signaling to ECs.