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

Abstract

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.

An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris

“…Consistent with this notion, COX2-deficient mice, which exhibit progressive choroidal degeneration, have been reported to display reduced VEGF expression (34). Inhibition of VEGF signaling has been shown to be associated with rapid loss of fenestration and EC apoptosis in a variety of tissues (6,8,10,35). Our observation of CC atrophy in mice expressing only VEGF188 is consistent with our hypothesis that the reduced ability of VEGF188 to diffuse through the BrM would impair CC survival.…”

“…For instance, in the lung where VEGF188 is the predominant isoform (17), VEGF is produced by type 2 pneumocytes, which are separated from the alveolar capillary endothelial cell by a very thin basement membrane, a arrangement that maximizes oxygen diffusion. On the other hand, in the choroid plexus of the brain, the epithelium produces primarily VEGF120, which supports not only the underlying fenestrated microvasculature, but diffuses into the cerebral spinal fluid to act on the VEGFR2-expressing ependymal cell ventricular lining (10). The fact that RPE express only the soluble VEGF isoforms, VEGF120 and VEGF164, is consistent with the physical barrier posed by the presence of BrM elastic lamina between the VEGF-producing RPE cells and the target CC.…”

“…Vessel regression was also noted in the pancreas (8,9), trachea, thyroid, and small intestine (8). Recently, we have reported that systemic inhibition of VEGF using adenoviral expression of sFlt-1 leads to nonperfusion of vessels in the choroid plexus (10). The CC of the eye has been shown to be similarly vulnerable to VEGF inhibition.…”

“…Systemic VEGF neutralization in mice led to a breakdown of the ventricular barrier function, and a direct role for VEGF as a survival factor for ependymal cells was indicated by their expression of VEGFR2 (10). We recently demonstrated a paracrine relationship between Müller cell-derived VEGF and VEGFR2 expressing photoreceptors in the murine retina (14).…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…The formation and maintenance of the fenestrations and their diaphragms involve the plasmalemma vesicle associated protein (Plvap) gene [143] and are under the control of the choroidal epithelium via a basolateral secretion of vascular endothelial growth factor (VEGF). Neutralizing choroidal VEGF production leads to strong morphological and functional alterations of the choroidal vasculature, with presumable consequences on CSF secretion and composition [86]. This mechanism may underlie the central side effect of anti-VEGF antibodies observed in some patients under antitumoral therapy.…”