Abstract
Endothelial cells contain several nanoscale domains such as caveolae, fenestrations and transendothelial channels, which regulate signaling and transendothelial permeability. These structures can be covered by filter-like diaphragms. A transmembrane PLVAP (plasmalemma vesicle associated protein) protein has been shown to be necessary for the formation of diaphragms. The expression, subcellular localization and fenestra-forming role of PLVAP in liver sinusoidal endothelial cells (LSEC) have remained controversial. Here we show that fenestrations in LSEC contain PLVAP-diaphragms during the fetal angiogenesis, but they lose the diaphragms at birth. Although it is thought that PLVAP only localizes to diaphragms, we found luminal localization of PLVAP in adult LSEC using several imaging techniques. Plvap-deficient mice revealed that the absence of PLVAP and diaphragms did not affect the morphology, the number of fenestrations or the overall vascular architecture in the liver sinusoids. Nevertheless, PLVAP in fetal LSEC (fenestrations with diaphragms) associated with LYVE-1 (lymphatic vessel endothelial hyaluronan receptor 1), neuropilin-1 and VEGFR2 (vascular endothelial growth factor receptor 2), whereas in the adult LSEC (fenestrations without diaphragms) these complexes disappeared. Collectively, our data show that PLVAP can be expressed on endothelial cells without diaphragms, contradict the prevailing concept that biogenesis of fenestrae would be PLVAP-dependent, and reveal previously unknown PLVAP-dependent molecular complexes in LSEC during angiogenesis.
Highlights
Endothelial cells contain several nanoscale domains such as caveolae, fenestrations and transendothelial channels, which regulate signaling and transendothelial permeability
Since there are discrepant reports regarding the expression of PLVAP protein in liver[8,11,19,20,21,22,23,24], we used timed matings to get fetal and postnatal liver specimens from wild-type mice for re-evaluating the expression of PLVAP in liver sinusoidal endothelial cells (LSEC) during liver angiogenesis
Using an anti-PLVAP mAb MECA-32 and confocal microscopy analyses we found that PLVAP was expressed in virtually all LSEC before birth (Fig. 1a)
Summary
Endothelial cells contain several nanoscale domains such as caveolae, fenestrations and transendothelial channels, which regulate signaling and transendothelial permeability. These structures can be covered by filter-like diaphragms. Plvap-deficient mice revealed that the absence of PLVAP and diaphragms did not affect the morphology, the number of fenestrations or the overall vascular architecture in the liver sinusoids. While PLVAP is necessary for diaphragm formation, it is not sufficient for it This was shown in elegant experiments by Stan et al showing that forced pan-endothelial PLVAP expression in Plvap−/− mice did not result in diaphragm formation in those vascular beds in which PLVAP is not normally expressed[8]. In mice PLVAP regulates the permeability of subcapsular sinus lymphatic endothelial cells to leukocytes and antigens in peripheral lymph nodes[14], and the generation of fetal-derived macrophages in the fetal liver[18]
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