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 - PubMed (original) (raw)
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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
Esmeralda K Bosma et al. Fluids Barriers CNS. 2018.
Abstract
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.
Keywords: Blood–brain barrier; Blood–retinal barrier; Cerebral edema; Diabetic macular edema; Plasmalemma vesicle-associated protein.
Figures
Fig. 1
The PAL-E antibody stains endothelial vesicles. Immunogold labelling of cultured human endothelial cells from umbilical veins shows that the PAL-E antigen is associated with the exterior of endothelial vesicles (arrowheads and inset) (Reprinted from [22])
Fig. 2
PLVAP functions as physical sieve in endothelium. PLVAP homodimers assemble in diaphragms in a wheel-like fashion. The larger part of PLVAP is extracellular, but PLVAP dimers are stabilized in the cell membrane by prominent _N_-glycosylation near its transmembrane domain (not shown) and its intracellular connections to cytoskeletal filaments (not shown). Through this distinct organization, PLVAP regulates size-dependent passage of molecules. It is hypothesized that PLVAP allows the passage of molecules smaller than 6 nm in diameter only. EC endothelial cell, TEC transendothelial channel
Fig. 3
PLVAP regulates vascular development and function. a Absence of Wnt and Norrin ligands for the Lpr5/Frzd receptor complex results in inactive canonical β-catenin signaling in non-barrier endothelium and in early embryonic stages in barrier endothelium. As a consequence, cytosolic β-catenin is targeted for proteolytic degradation through phosphorylation by the “β-catenin destruction complex”, which consists of the APC/axin/GSK3b-complex. Low levels of β-catenin allow upregulation of PLVAP expression in endothelial cells. However, it is unknown how PLVAP expression is upregulated during vascular development. PLVAP expression in the developing vasculature is essential during angiogenesis. PLVAP may directly promote angiogenesis or give mechanical support to capillaries, which prevents the formation of leaky vessels after the drastic remodeling steps of angiogenesis. b The canonical β-catenin signaling pathway is active in late embryonic stages in barrier endothelium. In the presence of Wnt or Norrin ligands, the “β-catenin destruction complex” is inhibited which results in the accumulation of β-catenin in cells. Nuclear β-catenin induces the transcription of β-catenin-target genes, which results in the downregulation of PLVAP expression. Low levels of PLVAP expression induce maturation of the BRB and BBB. EC endothelial cell (Adapted from [68])
Fig. 4
PLVAP induces vascular leakage through promoting VEGF-dependent caveolae formation. a The BBB and inner BRB are hallmarked by high trans-endothelial electrical resistance (TEER), which is the result of an elaborated junctional network, limited presence of caveolae and absence of fenestrae. In physiological conditions, the availability of VEGFR1 homodimers predominantly localized at the luminal side of the BBB and BRB induces important vascular protective functions [120]. In contrast, VEGFR2 homodimers at the abluminal side [120], which are probably present at a very low concentration under physiological conditions, as VEGFR2 is usually not detectable by immunohistochemistry in brain and retinal vessels [74, 75], mediate vascular leakage (not shown). b In pathological conditions such as diabetic retinopathy, tissue VEGF-A levels are high. In addition, VEGFR2 and VEGFR3 are highly expressed in retinal vessels of diabetic patients. Together, this results in VEGFR2/PI3K/p38MAPK-dependent PLVAP expression and formation of caveolae, which promotes leakage of plasma proteins and edema formation. EC endothelial cell, PC pericyte
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