VEGFR‐3 in adult angiogenesis

Abstract

Vascular endothelial growth factor receptor 3 (VEGFR-3, Flt-4), the receptor for vascular endothelial growth factors (VEGFs) C and D, is expressed on lymphatic endothelium and may play a role in lymphangiogenesis. In embryonic life, VEGFR-3 is essential for blood vessel development. The purpose of this study was to investigate whether VEGFR-3 is also involved in blood vessel angiogenesis in the adult. This was studied in human tissues showing angiogenesis and in a model of VEGF-A-induced iris neovascularization in the monkey eye, by the use of immunohistochemistry at the light and electron microscopic level. VEGFR-3 was expressed on endothelium of proliferating blood vessels in tumours. In granulation tissue, staining was observed in the proliferative superficial zone in plump blood vessel sprouts, in the intermediate zone in blood vessels and long lymphatic sprouts, and in the deeper fibrous zone in large lymphatics, in a pattern demonstrating that lymphangiogenesis follows behind blood vessel angiogenesis in granulation tissue formation. At the ultrastructural level, VEGFR-3 was localized in the cytoplasm and on the cell membrane of endothelial cells of sprouting blood vessels and sprouting lymphatics. In monkey eyes injected with VEGF-A, blood vessel sprouts on the anterior iris surface and pre-existing blood vessels in the iris expressed VEGFR-3. In conclusion, these results support a role for VEGFR-3 and its ligands VEGF-C and/or VEGF-D in cell-to-cell signalling in adult blood vessel angiogenesis. The expression of VEGFR-3 in VEGF-A-induced iris neovascularization and in pre-existing blood vessels exposed to VEGF-A suggests that this receptor and possibly its ligands are recruited in VEGF-A-driven angiogenesis.

Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex

“…angiogenesis but is otherwise low in stable arteries (Gu et al, 2001;Witmer et al, 2001;Tammela et al, 2008). However, we found that its mRNA was readily detectable in the normal mouse aorta, and a reporter construct was up regulated at the inner curvature of the aortic arch that is exposed to disturbed shear stress.…”

“…VEGFR3 is expressed in lymphatic endothelial cells (Karkkainen et al, 2000) and angiogenic endothelium (Kubo et al, 2000;Gu et al, 2001;Witmer et al, 2001; Tammela et al, Ncad and VEcad chimeras to identify the sequences required for shear stress mechanotransduction. This approach led to the surprising result that the TMD is the critical VEcad specific se quence.…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…For example, the expression of VEGFR-3 is detectable in BECs before lymphatic sprouting, but after then is restricted to LECs, thus serving as an important LECsignature gene in normal tissues (Jeltsch et al 1997). However, abnormal expression of VEGFR-3 in BECs has been reported in various malignant tumors and granulation tissues (Partanen et al 1999;Valtola et al 1999;Witmer et al 2001;Nakamura et al 2003). Thus, VEGFR-3 expression in BECs was postulated to be a new microvascular progression marker that mediates lymphangiogenic factor-induced neovascularization (Clarijs et al 2002).…”

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

“…Air-dried serial cryostat sections (8 m thick) were fixed in cold acetone for 10 min and stained by an indirect immunoperoxidase procedure (Witmer et al 2001), using the following antibodies: monoclonal antibodies (MAb) Flt-19 (against VEGFR-1, dilution 1:400) and KDR-1 (against VEGFR-2, dilution 1:400) (Simon et al 1998), MAb 9D9F9 (against VEGFR-3, dilution 1:1500) (Lymboussaki et al 1998), and the anti-endothelial MAbs PAL-E (dilution 1:1000) (Schlingemann et al 1985) and EN-4 (against CD31; dilution 1:500) (Ruiter et al 1989). Flt-19 and KDR-1 were kindly provided by Dr. H.A.…”