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Plasmalemma vesicle-associated protein: A crucial component of vascular homeostasis

View Article: PubMed Central - PubMed

ABSTRACT

Endothelial subcellular structures, including caveolae, fenestrae and transendothelial channels, are crucial for regulating microvascular function. Plasmalemma vesicle-associated protein (PLVAP) is an endothelial cell-specific protein that forms the stomatal and fenestral diaphragms of blood vessels and regulates basal permeability, leukocyte migration and angiogenesis. Loss of PLVAP in mice leads to premature mortality due to disrupted homeostasis. Evidence from previous studies suggested that PLVAP is involved in cancer, traumatic spinal cord injury, acute ischemic brain disease, transplant glomerulopathy, Norrie disease and diabetic retinopathy. Specifically, PLVAP expression has been demonstrated to be upregulated in these diseases, accompanied by pro-angiogenic or pro-inflammatory responses. Therefore, PLVAP is considered a novel therapeutic target, in addition to an endothelial cell marker. The present review summarizes the structure and functions of PLVAP, and its roles in pathophysiological processes.

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Regulation of PLVAP expression. VEGF signaling stimulates the expression of PLVAP via activation of the PI3K and p38MAPK signaling pathways. The PI3K inhibitor LY294002 and p38MAPK inhibitor SB203580 decrease the mRNA and protein expression levels of PLVAP. PLVAP, plasmalemma vesicle-associated protein; VEGF, vascular endothelial growth factor; PI3K, phosphatidylinositol 3-kinase; p38MAPK, p38 mitogen-activated protein kinase; VEGFR-2, vascular endothelial growth factor receptor-2; TECs, transendothelial channels; MKK3/6, mitogen-activated protein kinase kinase 3/6.
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f2-etm-0-0-3557: Regulation of PLVAP expression. VEGF signaling stimulates the expression of PLVAP via activation of the PI3K and p38MAPK signaling pathways. The PI3K inhibitor LY294002 and p38MAPK inhibitor SB203580 decrease the mRNA and protein expression levels of PLVAP. PLVAP, plasmalemma vesicle-associated protein; VEGF, vascular endothelial growth factor; PI3K, phosphatidylinositol 3-kinase; p38MAPK, p38 mitogen-activated protein kinase; VEGFR-2, vascular endothelial growth factor receptor-2; TECs, transendothelial channels; MKK3/6, mitogen-activated protein kinase kinase 3/6.

Mentions: Vascular endothelial growth factor (VEGF), which stimulates increased vascular permeability and angiogenesis, is the primary regulator of PLVAP (33). However, the reports of the effects of VEGF on PLVAP expression have been conflicting. Hofman et al (34) suggested that PLVAP was directly or indirectly induced by VEGF, as VEGF and PLVAP (the then PAL-E) were revealed to simultaneously be present on the retina of diabetic patients with retinal vascular leakage. Consistent with this, Strickland et al (33) demonstrated that treatment of human umbilical vein ECs (HUVECs) with VEGF increased the mRNA and protein expression levels of PLVAP via activation of the VEGF receptor 2 (33). Furthermore, this effect was attenuated by an anti-VEGF monoclonal antibody, and was reported to be mediated via the phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways (33) (Fig. 2). In addition, treatment with the PI3K inhibitor LY294002 or the p38MAPK inhibitor SB203580 induced a dose-dependent decrease in the mRNA and protein expression levels of PLVAP (33). However, experiments using caveolin-1− mice suggested that PLVAP expression in the lungs was negatively regulated by VEGF (35). Notably, the PLVAP expression level remained unchanged in caveolin-2- mice under identical experimental conditions (35). These seemingly contradictory results suggested that other endothelial proteins, such as caveolin-1, may affect VEGF-mediated regulation of PLVAP expression. In addition, the effects of increased VEGF expression on PLVAP expression may vary across different organs and/or species (33,35). PLVAP expression has also been shown to be regulated by phorbol myristate acetate (PMA), an activator of protein kinase C (14). The treatment of EC cultures with PMA resulted in the upregulation of PLVAP expression in a dose-dependent and time-dependent manner (14). Furthermore, PMA-induced upregulation of PLVAP expression was hypothesized to be dependent on the activation of the extracellular signal-regulated protein kinase 1/2-MAPK signaling pathway (14).


Plasmalemma vesicle-associated protein: A crucial component of vascular homeostasis
Regulation of PLVAP expression. VEGF signaling stimulates the expression of PLVAP via activation of the PI3K and p38MAPK signaling pathways. The PI3K inhibitor LY294002 and p38MAPK inhibitor SB203580 decrease the mRNA and protein expression levels of PLVAP. PLVAP, plasmalemma vesicle-associated protein; VEGF, vascular endothelial growth factor; PI3K, phosphatidylinositol 3-kinase; p38MAPK, p38 mitogen-activated protein kinase; VEGFR-2, vascular endothelial growth factor receptor-2; TECs, transendothelial channels; MKK3/6, mitogen-activated protein kinase kinase 3/6.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4998186&req=5

f2-etm-0-0-3557: Regulation of PLVAP expression. VEGF signaling stimulates the expression of PLVAP via activation of the PI3K and p38MAPK signaling pathways. The PI3K inhibitor LY294002 and p38MAPK inhibitor SB203580 decrease the mRNA and protein expression levels of PLVAP. PLVAP, plasmalemma vesicle-associated protein; VEGF, vascular endothelial growth factor; PI3K, phosphatidylinositol 3-kinase; p38MAPK, p38 mitogen-activated protein kinase; VEGFR-2, vascular endothelial growth factor receptor-2; TECs, transendothelial channels; MKK3/6, mitogen-activated protein kinase kinase 3/6.
Mentions: Vascular endothelial growth factor (VEGF), which stimulates increased vascular permeability and angiogenesis, is the primary regulator of PLVAP (33). However, the reports of the effects of VEGF on PLVAP expression have been conflicting. Hofman et al (34) suggested that PLVAP was directly or indirectly induced by VEGF, as VEGF and PLVAP (the then PAL-E) were revealed to simultaneously be present on the retina of diabetic patients with retinal vascular leakage. Consistent with this, Strickland et al (33) demonstrated that treatment of human umbilical vein ECs (HUVECs) with VEGF increased the mRNA and protein expression levels of PLVAP via activation of the VEGF receptor 2 (33). Furthermore, this effect was attenuated by an anti-VEGF monoclonal antibody, and was reported to be mediated via the phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways (33) (Fig. 2). In addition, treatment with the PI3K inhibitor LY294002 or the p38MAPK inhibitor SB203580 induced a dose-dependent decrease in the mRNA and protein expression levels of PLVAP (33). However, experiments using caveolin-1− mice suggested that PLVAP expression in the lungs was negatively regulated by VEGF (35). Notably, the PLVAP expression level remained unchanged in caveolin-2- mice under identical experimental conditions (35). These seemingly contradictory results suggested that other endothelial proteins, such as caveolin-1, may affect VEGF-mediated regulation of PLVAP expression. In addition, the effects of increased VEGF expression on PLVAP expression may vary across different organs and/or species (33,35). PLVAP expression has also been shown to be regulated by phorbol myristate acetate (PMA), an activator of protein kinase C (14). The treatment of EC cultures with PMA resulted in the upregulation of PLVAP expression in a dose-dependent and time-dependent manner (14). Furthermore, PMA-induced upregulation of PLVAP expression was hypothesized to be dependent on the activation of the extracellular signal-regulated protein kinase 1/2-MAPK signaling pathway (14).

View Article: PubMed Central - PubMed

ABSTRACT

Endothelial subcellular structures, including caveolae, fenestrae and transendothelial channels, are crucial for regulating microvascular function. Plasmalemma vesicle-associated protein (PLVAP) is an endothelial cell-specific protein that forms the stomatal and fenestral diaphragms of blood vessels and regulates basal permeability, leukocyte migration and angiogenesis. Loss of PLVAP in mice leads to premature mortality due to disrupted homeostasis. Evidence from previous studies suggested that PLVAP is involved in cancer, traumatic spinal cord injury, acute ischemic brain disease, transplant glomerulopathy, Norrie disease and diabetic retinopathy. Specifically, PLVAP expression has been demonstrated to be upregulated in these diseases, accompanied by pro-angiogenic or pro-inflammatory responses. Therefore, PLVAP is considered a novel therapeutic target, in addition to an endothelial cell marker. The present review summarizes the structure and functions of PLVAP, and its roles in pathophysiological processes.

No MeSH data available.


Related in: MedlinePlus