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Journal of Histochemistry and Cytochemistry, Vol. 48, 545-556, April 2000, Copyright © 2000, The Histochemical Society, Inc.

ARTICLE

Ultrastructural Localization of the Vascular Permeability Factor/Vascular Endothelial Growth Factor (VPF/VEGF) Receptor-2 (FLK-1, KDR) in Normal Mouse Kidney and in the Hyperpermeable Vessels Induced by VPF/VEGF-expressing Tumors and Adenoviral Vectors

Dian Fenga, Janice A. Nagya, Rolf A. Brekkenc, Anna Petterssonb, Eleanor J. Manseaua, Kathryn Pynea, Richard Mulliganb, Philip E. Thorpec, Harold F. Dvoraka, and Ann M. Dvoraka
a Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
b Howard Hughes Medical Institute, Children's Hospital, and Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts
c Hamon Center for Therapeutic Oncology Research and the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas

Correspondence to: Ann M. Dvorak, Dept. of Pathology, East Campus, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: advorak@caregroup.harvard.edu

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) interacts with two high-affinity tyrosine kinase receptors, VEGFR-1 and VEGFR-2, to increase microvascular permeability and induce angiogenesis. Both receptors are selectively expressed by vascular endothelial cells and are strikingly increased in tumor vessels. We used a specific antibody to localize VEGFR-2 (FLK-1, KDR) in microvascular endothelium of normal mouse kidneys and in the microvessels induced by the TA3/St mammary tumor or by infection with an adenoviral vector engineered to express VPF/VEGF. A pre-embedding method was employed at the light and electron microscopic levels using either nanogold or peroxidase as reporters. Equivalent staining was observed on both the luminal and abluminal surfaces of tumor- and adenovirus-induced vascular endothelium, but plasma membranes at interendothelial junctions were spared except at sites connected to vesiculovacuolar organelles (VVOs). VEGFR-2 was also localized to the membranes and stomatal diaphragms of some VVOs. This staining distribution is consistent with a model in which VPF/VEGF increases microvascular permeability by opening VVOs to allow the transendo–thelial cell passage of plasma and plasma proteins. (J Histochem Cytochem 48:545–555,2000)

Key Words: vascular permeability factor, (VPF), vascular endothelial growth, factor (VEGF), vascular permeability factor, receptor (VPFR), vascular endothelial growth, factor receptor (VEGFR), fetal liver kinase 1 (Flk-1), kinase insert domain- containing receptor (KDR), ultrastructure, immunocytochemistry, endothelial cells, tumor vessels, mouse kidney, vesiculovacuolar organelle, (VVO)


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