Fibulin-1 is required for microvascular integrity in the developing brain and retina

Vascularization of the central nervous system and the postnatal retina proceeds through angiogenic growth that relies in part on the basement membrane (BM) to support endothelial cell-cell interactions and maintain barrier integrity during vessel formation. In addition to the core structural components of the BM, matricellular proteins are present as minor constituents, however, their contributions to endothelial cohesion and barrier stability during angiogenesis remain poorly defined. Here, we identify the matricellular protein Fibulin-1 (Fbln1), a regulator of cell-matrix interactions, as an essential factor during mid-gestation that prevents the formation of dilated, tortuous capillaries that give rise to glomeruloid vascular lesions and intracerebral hemorrhage. Fbln1-deficient brains exhibit vascular malformations characterized by reduced type IV collagen deposition and diminished CD31 localization at endothelial junctions. Although overall pericyte coverage across the vasculature is maintained, the glomeruloid lesions lack pericyte investment. In the developing retina, loss of Fbln1 similarly results in hemorrhage and tortuous capillaries with glomeruloid vascular abnormalities that disrupt the formation of both the superficial and deep vascular plexuses. Together, these findings demonstrate that Fbln1 is a critical determinant of brain and retinal vascular development and is required to preserve endothelial barrier integrity during angiogenesis.