Vascular Expression of Endothelial Antigen PAL-E Indicates Absence of Blood-Ocular Barriers in the Normal Eye

Ro, Schlingemann; Hofman, P; Anderson, Lakin; Troost, Dirk; R, van der Gaag

doi:10.1159/000268007

Cited by 30 publications

(31 citation statements)

References 21 publications

(35 reference statements)

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“…We also found that loss of the blood-retina barrier in DR is associated with increased expression of the PAL-E antigen in retinal capillary endothelium [18]. This may be based on changes in the number and/or structure of the pinocytotic vesicles of endothelial cells, as at the ultrastructural level, the endothelium-specific PAL-E antigen is located in pinocytotic vesicles [19][20][21]. In other pathological conditions characterised by loss of the blood-brain barrier, such as primary and metastiatic brain tumours, PAL-E also appears in the endothelium of leaky vessels [19,22,23].…”

Section: Introductionmentioning

confidence: 55%

“…It is expressed by fenestrated and most continuous endothelia of vessels with non-specific permeability for plasma proteins. Endothelium in sites with a blood-brain barrier, including retina and iris, lacks the antigen [20,21]. In pathological conditions with loss of the blood-brain barrier, like brain tumors, but also in DR, PAL-E appears in the leaky endothelium [18,19,22,23].…”

Section: Discussionmentioning

confidence: 99%

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Role of VEGF-A in Endothelial Phenotypic Shift in Human Diabetic Retinopathy and VEGF-A-Induced Retinopathy in Monkeys

et al. 2001

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The endothelium-specific antigen PAL-E, associated with transport vesicles in non-barrier endothelium, is almost absent from barrier capillaries in the normal brain and retina. We have recently demonstrated that only leaking retinal capillaries in diabetic retinopathy (DR) in humans characteristically express PAL-E. Here we investigated the relation between the expression of the PAL-E antigen and vascular endothelial growth factor-A (VEGF) in human post-mortem eyes of individuals with diabetes mellitus (DM) and in experimental VEGF-induced retinopathy in cynomolgus monkeys. Cryosections were cut of eyes of 41 individuals with and 30 individuals without DM and eyes of 2 cynomolgus monkeys who received 4 injections of 0.5 µg VEGF in the vitreous of one eye and PBS in the other. The sections were stained with antibodies against VEGF, PAL-E and endogenous markers for microvascular leakage. Specific retinal vascular staining for VEGF was only observed in 10 out of the 41 cases with DM. These 10 cases also had marked uniform PAL-E staining and widespread vascular leakage. In contrast, diabetic patients without microvascular leakage and controls were negative for VEGF and PAL-E. Likewise, PAL-E was found only in the leaky retinal vessels of monkey eyes injected with VEGF. These results indicate that increased expression of the PAL-E antigen in retinal endothelium in conditions with microvascular leakage is related to VEGF and suggest that VEGF directly or indirectly induces PAL-E. PAL-E expression may reflect important endothelial changes involved in the disturbance of the blood-retina barrier in DR.

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Section: Introductionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Role of VEGF-A in Endothelial Phenotypic Shift in Human Diabetic Retinopathy and VEGF-A-Induced Retinopathy in Monkeys

et al. 2001

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“…The similarity in phenotype is shown by our immunohistochemical findings, as we found expression of two BBB markers which are both functionally involved in the blood-brain barrier, Glucose-transporter-1 and PGlycoprotein, and lack of expression of the PAL-E antigen in the iris and ciliary muscle capillaries. The endothelium specific PAL-E antigen is absent from normal BBB endothelium in the brain and eye (Schlingemann et al, 1988(Schlingemann et al, , 1997Leenstra et al, 1993) and is associated with pinocytotic vesicles which are scarce in BBB endothelium (Reese and Karnovsky, 1967 ;Schlingemann et al, 1985Schlingemann et al, , 1991. Functionally, our tracer study in the rabbit showed that ciliary muscle capillaries are impermeable for HRP.…”

Section: Discussionmentioning

confidence: 99%

“…In areas with a patent blood-tissue barrier the antigen is not found. The PAL-E antigen therefore appears to be a marker indicating sites with an absent blood-tissue barrier (Schlingemann et al, 1988(Schlingemann et al, , 1997.…”

Section: Introductionmentioning

confidence: 99%

Ciliary Muscle Capillaries Have Blood–Tissue Barrier Characteristics

Schlingemann

Hofman

Klooster

et al. 1998

Experimental Eye Research

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“…Staining of serial sections with PAL-E was performed to identify capillaries and venules that are not involved in a blood-tissue barrier, whereas this antigen is absent in lymphatic endothelium. Anti-CD31 was used as a marker for all blood and lymph vessel endothelium (Schlingemann et al 1985(Schlingemann et al ,1997Ruiter et al 1989).…”

Section: Light Microscopic Immunohistochemistrymentioning

confidence: 99%

Expression of Vascular Endothelial Growth Factor Receptors 1, 2, and 3 in Quiescent Endothelia

Witmer

Dai

Weich³

et al. 2002

J Histochem Cytochem.

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140

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The vascular endothelial growth factor (VEGF) family is involved in angiogenesis, and therefore VEGFs are considered as targets for anti-angiogenic therapeutic strategies against cancer. However, the physiological functions of VEGFs in quiescent tissues are unclear and may interfere with such systemic therapies. In pathological conditions, increased levels of expression of the VEGF receptors VEGFR-1, VEGFR-2, and VEGFR-3 accompany VEGF activity. In this study we investigated normal human and monkey tissues for expression patterns of these receptors. Immunohistochemical staining methods at the light and electron microscopic level were applied to normal human and monkey tissue samples, using monoclonal antibodies (MAbs) against the three VEGFRs and anti-endothelial MAbs PAL-E and anti-CD31 to identify blood and lymph vessels. In human and monkey, similar distribution patterns of the three VEGFRs were found. Co-expression of VEGFR-1, −2, and −3 was observed in microvessels adjacent to epithelia in the eye, gastrointestinal mucosa, liver, kidney, and hair follicles, which is in line with the reported preferential expression of VEGF-A in some of these epithelia. VEGFR-1, −2, and −3 expression was also observed in blood vessels and sinusoids of lymphoid tissues. Furthermore, VEGFR-1, but not VEGFR-2 and −3, was present in microvessels in brain and retina. Electron microscopy showed that VEGFR-1 expression was restricted to pericytes and VEGFR-2 to endothelial cells in normal vasculature of tonsils. These findings indicate that VEGFRs have specific distribution patterns in normal tissues, suggesting physiological functions of VEGFs that may be disturbed by systemic anti-VEGF therapy. One of these functions may be involvement of VEGF in paracrine relations between epithelia and adjacent capillaries.

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Vascular Expression of Endothelial Antigen PAL-E Indicates Absence of Blood-Ocular Barriers in the Normal Eye

Cited by 30 publications

References 21 publications

Role of VEGF-A in Endothelial Phenotypic Shift in Human Diabetic Retinopathy and VEGF-A-Induced Retinopathy in Monkeys

Role of VEGF-A in Endothelial Phenotypic Shift in Human Diabetic Retinopathy and VEGF-A-Induced Retinopathy in Monkeys

Ciliary Muscle Capillaries Have Blood–Tissue Barrier Characteristics

Expression of Vascular Endothelial Growth Factor Receptors 1, 2, and 3 in Quiescent Endothelia

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