The Journal of Experimental Medicine
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Published online February 11, 2008
doi:10.1084/jem.20072041
The Journal of Experimental Medicine, Vol. 205, No. 2, 491-501
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Maharaj et al.
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ARTICLE

VEGF and TGF-β are required for the maintenance of the choroid plexus and ependyma

Arindel S.R. Maharaj3,4, Tony E. Walshe3,4, Magali Saint-Geniez3,4, Shivalingappa Venkatesha4,5, Angel E. Maldonado3,4, Nathan C. Himes4, Kabir S. Matharu3, S. Ananth Karumanchi4,5, and Patricia A. D'Amore1,2,3,4

1 Department of Ophthalmology, 2 Department of Pathology, and 3 Schepens Eye Research Institute, 4 Harvard Medical School, Boston, MA 02114
5 Beth Israel Deaconess Medical Center, Boston, MA 02215

CORRESPONDENCE Patricia A. D'Amore: patricia.damore{at}schepens.harvard.edu

Although the role of vascular endothelial growth factor (VEGF) in developmental and pathological angiogenesis is well established, its function in the adult is less clear. Similarly, although transforming growth factor (TGF) β is involved in angiogenesis, presumably by mediating capillary (endothelial cell [EC]) stability, its involvement in quiescent vasculature is virtually uninvestigated. Given the neurological findings in patients treated with VEGF-neutralizing therapy (bevacizumab) and in patients with severe preeclampsia, which is mediated by soluble VEGF receptor 1/soluble Fms-like tyrosine kinase receptor 1 and soluble endoglin, a TGF-β signaling inhibitor, we investigated the roles of VEGF and TGF-β in choroid plexus (CP) integrity and function in adult mice. Receptors for VEGF and TGF-β were detected in adult CP, as well as on ependymal cells. Inhibition of VEGF led to decreased CP vascular perfusion, which was associated with fibrin deposition. Simultaneous blockade of VEGF and TGF-β resulted in the loss of fenestrae on CP vasculature and thickening of the otherwise attenuated capillary endothelium, as well as the disappearance of ependymal cell microvilli and the development of periventricular edema. These results provide compelling evidence that both VEGF and TGF-β are involved in the regulation of EC stability, ependymal cell function, and periventricular permeability.


Abbreviations used: Ad, adenovirus; CNS, central nervous system; coll IV, type IV collagen; CP, choroid plexus; CSF, cerebrospinal fluid; EC, endothelial cell; Gd, gadopentetate dimeglumine; H + E, hematoxylin and eosin; MRI, magnetic resonance imaging; RPLS, reversible posterior leukoencephalopathy syndrome; sEng, soluble endoglin; sFlt1, soluble Fms-like tyrosine kinase receptor 1; TEM, transmission electron microscopy; VEGF, vascular endothelial growth factor; VP, viral particles.

A.S.R. Maharaj and T.E. Walshe contributed equally to this work.


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