PV-1 is recognized by the PAL-E antibody and forms complexes with NRP-1

Keuschnigg, Johannes; Tvorogov, Denis; Elima, Kati; Salmi, Marko; Alitalo, Kari; Salminen, Tiina A.; Jalkanen, Sirpa

doi:10.1182/blood-2012-01-406876

Cited by 17 publications

(15 citation statements)

References 23 publications

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“…Our data that show the expression of mRNA for Plvap in the mouse liver, albeit at levels that are lower than in organs harboring capillaries with abundant endothelial diaphragms, are essentially comparable to findings of others, which detected Plvap mRNA in rat, mouse or human liver [13] , [15] , [30] . Moreover, similar to our results in the mouse liver, immunoreactivity for PLVAP localizes specifically to sinusoidal endothelial cells in the human liver [31] , strongly indicating that its function has been conserved throughout evolution. The important role of PLVAP in transcellular pore formation appears not to be restricted to the formation of fenestrations in the liver.…”

Section: Discussionsupporting

confidence: 89%

Formation of Fenestrae in Murine Liver Sinusoids Depends on Plasmalemma Vesicle-Associated Protein and Is Required for Lipoprotein Passage

et al. 2014

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Liver sinusoidal endothelial cells (LSEC) are characterized by the presence of fenestrations that are not bridged by a diaphragm. The molecular mechanisms that control the formation of the fenestrations are largely unclear. Here we report that mice, which are deficient in plasmalemma vesicle-associated protein (PLVAP), develop a distinct phenotype that is caused by the lack of sinusoidal fenestrations. Fenestrations with a diaphragm were not observed in mouse LSEC at three weeks of age, but were present during embryonic life starting from embryonic day 12.5. PLVAP was expressed in LSEC of wild-type mice, but not in that of Plvap-deficient littermates. Plvap-/- LSEC showed a pronounced and highly significant reduction in the number of fenestrations, a finding, which was seen both by transmission and scanning electron microscopy. The lack of fenestrations was associated with an impaired passage of macromolecules such as FITC-dextran and quantum dot nanoparticles from the sinusoidal lumen into Disse's space. Plvap-deficient mice suffered from a pronounced hyperlipoproteinemia as evidenced by milky plasma and the presence of lipid granules that occluded kidney and liver capillaries. By NMR spectroscopy of plasma, the nature of hyperlipoproteinemia was identified as massive accumulation of chylomicron remnants. Plasma levels of low density lipoproteins (LDL) were also significantly increased as were those of cholesterol and triglycerides. In contrast, plasma levels of high density lipoproteins (HDL), albumin and total protein were reduced. At around three weeks of life, Plvap-deficient livers developed extensive multivesicular steatosis, steatohepatitis, and fibrosis. PLVAP is critically required for the formation of fenestrations in LSEC. Lack of fenestrations caused by PLVAP deficiency substantially impairs the passage of chylomicron remnants between liver sinusoids and hepatocytes, and finally leads to liver damage.

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Section: Discussionsupporting

confidence: 89%

Formation of Fenestrae in Murine Liver Sinusoids Depends on Plasmalemma Vesicle-Associated Protein and Is Required for Lipoprotein Passage

et al. 2014

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“…Flow cytometric analyses indeed confirmed the expression of established BEC markers PAL-E and CD31 on both cell types (Figure 1A). Both, the anti-PV-1 antibody and PAL-E recognize PV-1, albeit different epitopes [11,12]. The shift of the entire peak when compared to the negative control indicates low-level expression of PV-1 in all cells.…”

Section: Resultsmentioning

confidence: 99%

“…To that end we examined how the new markers relate to the established vascular marker PV-1 [12] and lymphatic markers CLEVER-1 [13] (common lymphatic endothelial and vascular endothelial receptor-1), LYVE-1 and podoplanin in immunohistochemical stainings (Figure 5). The new BEC marker MCAM colocalized very well with the established blood vascular marker PV-1 (the epitope of the widely used antibody PAL-E; pathologische anatomie leiden-endothelium [12]), while there was no overlap with the staining pattern of the LEC markers CLEVER-1 and podoplanin. Similarly, the new LEC marker COLEC12 showed the expected staining pattern with colocalization with CLEVER-1 and LYVE-1 and mutually exclusive staining with PV-1.…”

Section: Resultsmentioning

confidence: 99%

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Plasticity of Blood- and Lymphatic Endothelial Cells and Marker Identification

et al. 2013

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The distinction between lymphatic and blood vessels is biologically fundamental. Here we wanted to rigorously analyze the universal applicability of vascular markers and characteristics of the two widely used vascular model systems human microvascular endothelial cell line-1 (HMEC-1) and telomerase-immortalized microvascular endothelial cell line (TIME). Therefore we studied the protein expression and functional properties of the endothelial cell lines HMEC-1 and TIME by flow cytometry and in vitro flow assays. We then performed microarray analyses of the gene expression in these two cell lines and compared them to primary endothelial cells. Using bioinformatics we then defined 39 new, more universal, endothelial-type specific markers from 47 primary endothelial microarray datasets and validated them using immunohistochemistry with normal and pathological tissues. We surprisingly found that both HMEC-1 and TIME are hybrid blood- and lymphatic cells. In addition, we discovered great discrepancies in the previous identifications of blood- and lymphatic endothelium-specific genes. Hence we identified and validated new, universally applicable vascular markers. Summarizing, the hybrid blood-lymphatic endothelial phenotype of HMEC-1 and TIME is indicative of plasticity in the gene expression of immortalized endothelial cell lines. Moreover, we identified new, stable, vessel-type specific markers for blood- and lymphatic endothelium, useful for basic research and clinical diagnostics.

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“…More recently, the same research group as Niemela et al [ 27 ] provided the final evidence that PAL-E recognizes PLVAP and not NRP-1 [ 45 ]. With the use of double staining, Keuschnigg et al [ 45 ] showed that both PLVAP and NRP-1 colocalize with the PAL-E antigen in human tissues. However, significantly different staining patterns were obtained with PAL-E and anti-NRP-1 in heart and liver, whereas the staining patterns of PAL-E and 174/2 were identical in all human tissues analyzed.…”

Section: The History Of the Identification Of Plvapmentioning

confidence: 99%

The role of plasmalemma vesicle-associated protein in pathological breakdown of blood–brain and blood–retinal barriers: potential novel therapeutic target for cerebral edema and diabetic macular edema

Bosma

Noorden

Schlingemann

et al. 2018

Fluids Barriers CNS

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Breakdown of the blood–brain barrier (BBB) or inner blood–retinal barrier (BRB), induced by pathologically elevated levels of vascular endothelial growth factor (VEGF) or other mediators, can lead to vasogenic edema and significant clinical problems such as neuronal morbidity and mortality, or vision loss. Restoration of the barrier function with corticosteroids in the brain, or by blocking VEGF in the eye are currently the predominant treatment options for brain edema and diabetic macular edema, respectively. However, corticosteroids have side effects, and VEGF has important neuroprotective, vascular protective and wound healing functions, implying that long-term anti-VEGF therapy may also induce adverse effects. We postulate that targeting downstream effector proteins of VEGF and other mediators that are directly involved in the regulation of BBB and BRB integrity provide more attractive and safer treatment options for vasogenic cerebral edema and diabetic macular edema. The endothelial cell-specific protein plasmalemma vesicle-associated protein (PLVAP), a protein associated with trans-endothelial transport, emerges as candidate for this approach. PLVAP is expressed in a subset of endothelial cells throughout the body where it forms the diaphragms of caveolae, fenestrae and trans-endothelial channels. However, PLVAP expression in brain and eye barrier endothelia only occurs in pathological conditions associated with a compromised barrier function such as cancer, ischemic stroke and diabetic retinopathy. Here, we discuss the current understanding of PLVAP as a structural component of endothelial cells and regulator of vascular permeability in health and central nervous system disease. Besides providing a perspective on PLVAP identification, structure and function, and the regulatory processes involved, we also explore its potential as a novel therapeutic target for vasogenic cerebral edema and retinal macular edema.

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PV-1 is recognized by the PAL-E antibody and forms complexes with NRP-1

Cited by 17 publications

References 23 publications

Formation of Fenestrae in Murine Liver Sinusoids Depends on Plasmalemma Vesicle-Associated Protein and Is Required for Lipoprotein Passage

Formation of Fenestrae in Murine Liver Sinusoids Depends on Plasmalemma Vesicle-Associated Protein and Is Required for Lipoprotein Passage

Plasticity of Blood- and Lymphatic Endothelial Cells and Marker Identification

The role of plasmalemma vesicle-associated protein in pathological breakdown of blood–brain and blood–retinal barriers: potential novel therapeutic target for cerebral edema and diabetic macular edema

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