Loss of the VEGF164 and VEGF188 Isoforms Impairs Postnatal Glomerular Angiogenesis and Renal Arteriogenesis in Mice

Abstract

ABSTRACT. Vascular endothelial growth factor (VEGF) is transcribed in the VEGF120, VEGF164, or VEGF188 isoforms, which differ in receptor binding, matrix association, and angiogenic activity. This vascular growth factor has been implicated in the development of the renal vasculature, but the role of the distinct VEGF isoforms remains unknown. In the present report, renal angiogenesis and arteriogenesis were studied in VEGF120/120 mice, expressing only the short VEGF120 isoform. In VEGF120/120 mice, ingrowth and survival of capillaries in glomeruli, remodeling of peritubular capillaries, vascular coverage by pericytes, and branching of renal arteries were all severely impaired, causing abnormal glomerular filtration and impairing renal function. The arterial branching defect might be related to a reduced expression of renin, a presumed renal arterial branching factor. Glomerulosclerosis and tubular dilation possibly resulted from renal ischemia caused by vascular defects. Thus, VEGF164 and VEGF188 not only mediate angiogenesis, but they also play an essential role in renal branching arteriogenesis.

CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island

“…When intraglomerular VEGF levels decrease in a transgenic mouse, capillary EC were found to swell, capillary loops collapsed, and proteinuria developed (60). Also, consistent with this observation, conditional VEGF isoform knockout mice are reported to have impaired glomerular filtration (39). Furthermore, in humans with preeclampsia it was found that circulating levels of a VEGF antagonist rise (36,40).…”

“…Increases in VEGF expression are well established to be functional for renal vasculogenesis and normal renal development in the embryo (30,39,64). However, recent data also suggest that VEGF has a major role in glomerular diseases (25,46,61).…”

Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis

“…Similarly, VEGF120 is capable of initiating the formation of the large axial vessels and the heart during mouse development (this study). However, during later stages of vascular development, when the fine patterning and positioning of vessels becomes critical for proper organogenesis, VEGF120 alone is insufficient: VEGF 120/120 mice exhibit discrete defects in the postnatal assembly of the myocardial vasculature, the kidney glomerulus, the lung epithelial-vascular interface, and the retinal vessel array (Carmeliet et al 1999;Ng et al 2001;Mattot et al 2002;Stalmans and Ng 2002).…”

Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered?

“…That is, when VEGF levels in the renal prodocytes drop 50%, glomerular endothelial cells swell, capillary loops collapse, and proteinuria developsas in preeclampsia. We previously demonstrated that absence of the VEGF 164 and VEGF 188 isoforms impairs glomerular filtration (9). Endothelial dysfunction may also deregulate hemostasis and trigger thrombocytopenia.…”