Neural deletion of Tgfbr2 impairs angiogenesis through an altered secretome.

Human molecular genetics

PubMedID: 24990151

Hellbach N, Weise SC, Vezzali R, Wahane SD, Heidrich S, Roidl D, Pruszak J, Esser JS, Vogel T. Neural deletion of Tgfbr2 impairs angiogenesis through an altered secretome. Hum Mol Genet. 2014;.
Simultaneous generation of neural cells and of the nutrient-supplying vasculature during brain development is called neurovascular coupling. We report on a transgenic mouse with impaired transforming-growth-factor ß (TGFß)-signalling in forebrain-derived neural cells using a Foxg1-cre knock-in to drive the conditional knock-out of the Tgfbr2. Although expression of FOXG1 is assigned to neural progenitors and neurons of the telencephalon, Foxg1(cre/+);Tgfbr2(flox/flox) (Tgfbr2-cKO) mutants displayed intracerebral haemorrhage. Blood vessels exhibited an atypical, clustered appearance, were less in number and displayed reduced branching. VEGFA, IGF1, IGF2, TGFß, ID1, THBS2, and ADAMTS1 were altered in either expression levels or tissue distribution. Accordingly, human umbilical vein endothelial cells (HUVEC) displayed branching defects after stimulation with conditioned medium (CM) that derived from primary neural cultures of the ventral and dorsal telencephalon of Tgfbr2-cKO. Supplementing CM of Tgfbr2-cKO with VEGFA rescued these defects, but application of TGFß aggravated them. HUVEC showed reduced migration towards CM of mutants compared to controls. Supplementing the CM with growth factors VEGFA, FGF2, and IGF1 partially restored HUVEC migration. In contrast, TGFß supplementation further impaired migration of HUVEC. We observed differences along the dorso-ventral axis of the telencephalon with regard to the impact of these factors on the phenotype. Together these data establish a TGFBR2-dependent molecular cross-talk between neural and endothelial cells during brain vessel development. These findings will be useful to further elucidate neurovascular interaction in general and to understand pathologies of the blood vessel system such as intracerebral haemorrhages, hereditary haemorrhagic telangiectasia, Alzheimer's disease, cerebral amyloid angiopathy or tumour biology.