Dartmouth scientists have demonstrated the importance of the gene Plvap and the structures it forms in mammalian physiology in a study published in December by the journal Developmental Cell.
"The knowledge generated and the animal models created will allow a better understanding of the role of the gene in diseases and will help validate its usefulness as a therapeutic or diagnostic target," said lead author Radu V. Stan, MD, associate professor, Geisel School of Medicine at Dartmouth, and member of the Dartmouth-Hitchcock Norris Cotton Cancer Center (NCCC).
The study demonstrates that plasmalemma vesicle associated protein (PV1), a vertebrate gene specifically expressed in the vascular endothelial cells, is critical for the formation of the diaphragms of endothelial caveolae, fenestrae and transendothelial channels. Although discovered in the 1960s by electron microscopy, the function of the diaphragms was previously unknown. Using mice with loss and gain of PV1 function Dartmouth scientists demonstrated that the diaphragms of fenestrae are critical for maintenance of basal permeability, the homeostasis of blood plasma in terms of protein and lipid blood composition, and ultimately survival.
PV1 has newly discovered roles in cancer and in various infectious and inflammatory diseases. "The knowledge generated and the animal models created will allow a better understanding of the role of the gene in these diseases and to validate its usefulness as a therapeutic or diagnostic target," said Stan.
In the absence of such diaphragms, plasma protein extravasation produces a noninflammatory protein-losing enteropathy resulting in protein calorie malnutrition and ultimately death.
"Our results and the mouse models we have created provide the foundations for evaluating numerous aspects of basal permeability in fenestrated vascular beds," said Stan.
The paper included two dozen Dartmouth authors from the Departments of Pathology, Microbiology and Immunology, Medicine, Genetics, Radiology, Experimental and Molecular Medicine, Heart and Vascular Research Center, and the Norris Cotton Cancer Center. This research was supported by NIH grants HL83249, HL092085, RR16437.
- Radu V. Stan, Dan Tse, Sophie J. Deharvengt, Nicole C. Smits, Yan Xu, Marcus R. Luciano, Caitlin L. McGarry, Maarten Buitendijk, Krishnamurthy V. Nemani, Raul Elgueta, Takashi Kobayashi, Samantha L. Shipman, Karen L. Moodie, Charles P. Daghlian, Patricia A. Ernst, Hong-Kee Lee, Arief A. Suriawinata, Alan R. Schned, Daniel S. Longnecker, Steven N. Fiering, Randolph J. Noelle, Barjor Gimi, Nicholas W. Shworak, Catherine Carrière. The Diaphragms of Fenestrated Endothelia: Gatekeepers of Vascular Permeability and Blood Composition. Developmental Cell, 2012; 23 (6): 1203 DOI: 10.1016/j.devcel.2012.11.003
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