Lack of endothelial diaphragms in fenestrae and caveolae of mutant Plvap-deficient mice.

Plasmalemmal vesicle-associated protein (PLVAP, PV-1) is specifically expressed in endothelial cells in which it localizes to diaphragms of fenestrae, caveolae, and transendothelial channels. To learn about its function, we generated mutant mice that lack PLVAP. In a C57BL/6N genetic background, homozygous Plvap-deficient embryos die before birth and suffer from subcutaneous edema, hemorrhages, and defects in the vascular wall of subcutaneous capillaries. In addition, hearts of Plvap(-/-) embryos show ventricular septal defects and thinner ventricular walls. In wild-type embryos, PLVAP and caveolae with a stomatal diaphragm are present in endothelial cells of subcutaneous capillaries and endocardium, while a diaphragm is missing in caveolae of Plvap(-/-) littermates. Plvap(-/-) mice in a mixed C57BL/6N/FVB-N genetic background are born and survive at the most for 4 weeks. Capillaries of exocrine and endocrine pancreas and of kidney peritubular interstitium were investigated in more detail as examples of fenestrated capillaries. In these vascular beds, Plvap(-/-) mice show a complete absence of diaphragms in fenestrae, caveolae, and transendothelial channels, findings which are associated with a substantial decrease in the number of endothelial fenestrae. The changes in the capillary phenotype correlate with a considerable retardation of postnatal growth and anemia. Plvap(-/-) mice provide an animal model to clarify the specific functional role of endothelial fenestrae and their contribution to passage of water and solutes in different organs.