Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms
Ingeborg Stalmans, Yin-Shan Ng, Richard Rohan, Marcus Fruttiger, Ann Bouché, Ali Ÿuce, Hajime Fujisawa, Bart Hermans, Moshe Shani, Sandra Jansen, Dan Hicklin, David J. Anderson, Tom Gardiner, Hans-Peter Hammes, Lieve Moons, Mieke Dewerchin, Désiré Collen, Peter Carmeliet, Patricia A. D’Amore
Ingeborg Stalmans, Yin-Shan Ng, Richard Rohan, Marcus Fruttiger, Ann Bouché, Ali Ÿuce, Hajime Fujisawa, Bart Hermans, Moshe Shani, Sandra Jansen, Dan Hicklin, David J. Anderson, Tom Gardiner, Hans-Peter Hammes, Lieve Moons, Mieke Dewerchin, Désiré Collen, Peter Carmeliet, Patricia A. D’Amore
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Article

Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms

Abstract

The murine VEGF gene is alternatively transcribed to yield the VEGF120, VEGF164, and VEGF188 isoforms, which differ in their potential to bind to heparan sulfate and neuropilin-1 and to stimulate endothelial growth. Here, their role in retinal vascular development was studied in mice selectively expressing single isoforms. VEGF164/164 mice were normal, healthy, and had normal retinal angiogenesis. In contrast, VEGF120/120 mice exhibited severe defects in vascular outgrowth and patterning, whereas VEGF188/188 mice displayed normal venular outgrowth but impaired arterial development. It is noteworthy that neuropilin-1, a receptor for VEGF164, was predominantly expressed in retinal arterioles. These findings reveal distinct roles of the various VEGF isoforms in vascular patterning and arterial development in the retina.

Authors

Ingeborg Stalmans, Yin-Shan Ng, Richard Rohan, Marcus Fruttiger, Ann Bouché, Ali Ÿuce, Hajime Fujisawa, Bart Hermans, Moshe Shani, Sandra Jansen, Dan Hicklin, David J. Anderson, Tom Gardiner, Hans-Peter Hammes, Lieve Moons, Mieke Dewerchin, Désiré Collen, Peter Carmeliet, Patricia A. D’Amore

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Retinal vascular development in VEGF+/+ and VEGF164/164 mice. (a) PECAM ...
Retinal vascular development in VEGF+/+ and VEGF164/164 mice. (a) PECAM staining in VEGF+/+ at P5. Capillaries reach two-thirds to three-quarters of the retinal radius. Arterioles (A) are thin and have a capillary-free zone. Venules (V) are broader and lack a capillary-free zone. La, arteriolar length; Lv, venular length; Lr, radius of retina; Lva, radius of vascular bed. (b and c) In situ hybridization for ephrin-B2 (EB2) (b) with or (c) without collagen type IV fluorescent immunostaining on VEGF+/+ retina at P5 (EB2/CollIV). EB2 expression is confined to morphologically defined arterioles (see above) and extends into arterial capillaries (arrows). (d and e) Triple staining with LacZ (in PECs, blue dots), lectin (in ECs, red), and anti-SMA (in vSMCs, green) on a VEGF+/+ × PECLacZ P5 retina (LacZ/Lec/SMA). (d) PECs have spread along all retinal vessels, whereas (e) only arterioles are SMA positive. (f) EM of VEGF+/+ capillary at P5, which appears constricted. (g) PECAM staining on VEGF+/+ P9 retina. (h) SMA staining in VEGF+/+ at P14 is confined to arterioles and their side branches. (i) VEGF+/+ × PECLacZ retina at 4 weeks. Hyaloid arteries (HA) have regressed (HA remnant, arrow). (j) Double staining for lectin (red) and GFAP (in ACs, green) (Lec/GFAP). AC network in front of vasculature. (k) PECAM staining of VEGF164/164 retina at P5. Normal vascular development.