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

Abstract

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.

Immunodetection and quantification of vascular endothelial growth factor receptor‐3 in human malignant tumor tissues

“…The result of the experiment was in good agreement with the report from Witmer et al 31 that showed that in normal kidney tissues, VEGFR-1 is present in glomerular or other capillaries, venule or veins, and in basement membrane in tubuli, while VEGFR-3 was present on capillaries and in lymphatics but not on venules, veins or basement membrane of tubuli.…”

The Lymphangiogenic Vascular Endothelial Growth Factors VEGF-C and -D Are Ligands for the Integrin α9β1

“…Cell Adhesion to VEGF-C and -D is ␣9␤1-Dependent-Adhesion assays were performed using ␣9-and mock-transfected MEF and SW-480 cells that do not express VEGF-R2 or -R3, (11,30) (data not shown). Flow cytometry with the anti-␣9␤1 antibody Y9A2 showed robust expression of ␣9␤1 in both ␣9-transfected cell types and no expression in mock transfectants ( Fig.…”

Anti-VEGF– and anti-VEGF receptor–induced vascular alteration in mouse healthy tissues

“…Abundant experimental data demonstrate that VEGFR-2 is the primary functional receptor that transduces both angiogenic and vascular permeability signals whereas VEGFR-1 may function as a decoy receptor (9,10). It should be emphasized that, under physiological and pathological conditions, VEGFR-2 is expressed not only in angiogenic vessels, but also in quiescent vasculatures in various tissues (11). The broad distribution of VEGFRs in quiescent vasculatures in various healthy tissues suggests that the VEGF-VEGFR signaling system is essential for maintenance of vascular homeostasis.…”