PMU-Autor/inn/en
Pruszak JanAbstract
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)
Animals
Blood-Brain Barrier/metabolism
Brain/blood supply
Brain/metabolism*
Brain/pathology
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
Humans
Insulin-Like Growth Factor I/metabolism
Mice
Mice, Transgenic
Neovascularization, Physiologic*
Nerve Tissue Proteins/genetics
Nerve Tissue Proteins/metabolism
Neural Stem Cells/metabolism
Neural Stem Cells/pathology
Neurons/metabolism*
Neurons/pathology
Pericytes/metabolism
Pericytes/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
Telencephalon/metabolism
Telencephalon/pathology
Transforming Growth Factor beta/metabolism
Vascular Endothelial Growth Factor A/metabolism