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Forschungsdatenbank PMU-SQQUID

Neural deletion of Tgfbr2 impairs angiogenesis through an altered secretome.
Hellbach, N; Weise, SC; Vezzali, R; Wahane, SD; Heidrich, S; Roidl, D; Pruszak, J; Esser, JS; Vogel, T;
Hum Mol Genet. 2014; 23(23):6177-6190
Originalarbeiten (Zeitschrift)


Pruszak Jan


Simultaneous generation of neural cells and that of the nutrient-supplying vasculature during brain development is called neurovascular coupling. We report on a transgenic mouse with impaired transforming growth factor β (TGFβ)-signalling in forebrain-derived neural cells using a Foxg1-cre knock-in to drive the conditional knock-out of the Tgfbr2. Although the 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. Vascular endothelial growth factor (VEGF) A, insulin-like growth factor (IGF) 1, IGF2, TGFβ, inhibitor of DNA binding (ID) 1, thrombospondin (THBS) 2, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 1 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 was 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 TGFβ aggravated them. HUVEC showed reduced migration towards CM of mutants compared with controls. Supplementing the CM with growth factors VEGFA, fibroblast growth factor (FGF) 2 and IGF1 partially restored HUVEC migration. In contrast, TGFβ 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 crosstalk 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, Alzheimeŕs disease, cerebral amyloid angiopathy or tumour biology.

Useful keywords (using NLM MeSH Indexing)


Blood-Brain Barrier/metabolism

Brain/blood supply



Cell Movement

Cerebral Hemorrhage/metabolism

Cerebral Hemorrhage/pathology

Culture Media, Conditioned

Fibroblast Growth Factor 2/metabolism

Forkhead Transcription Factors/genetics

Forkhead Transcription Factors/metabolism

Human Umbilical Vein Endothelial Cells/cytology

Human Umbilical Vein Endothelial Cells/metabolism


Insulin-Like Growth Factor I/metabolism


Mice, Transgenic

Neovascularization, Physiologic*

Nerve Tissue Proteins/genetics

Nerve Tissue Proteins/metabolism

Neural Stem Cells/metabolism

Neural Stem Cells/pathology





Protein-Serine-Threonine Kinases/genetics*

Protein-Serine-Threonine Kinases/metabolism

Receptor, Transforming Growth Factor-beta Type II

Receptors, Transforming Growth Factor beta/genetics*

Receptors, Transforming Growth Factor beta/metabolism

Secretory Pathway

Telencephalon/blood supply



Transforming Growth Factor beta/metabolism

Vascular Endothelial Growth Factor A/metabolism