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. 2000 May;156(5):1499-504.
doi: 10.1016/S0002-9440(10)65021-3.

Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing

K Paavonen  1 , P Puolakkainen, L Jussila, T Jahkola, K Alitalo
Affiliations

Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing

K Paavonen et al. Am J Pathol. 2000 May.

Abstract

Vascular endothelial growth factor receptor-3 (VEGFR-3) is essential for embryonic cardiovascular development, but thereafter becomes confined to the lymphatic endothelium in adult tissues. We have here studied VEGFR-3 expression in experimental wounds of pigs and chronic inflammatory wounds of humans. In healing incisional and punch biopsy wounds made in the dorsal skin of pigs, angiogenic blood vessels, identified by use of the blood vascular endothelial markers vWF and PAL-E and the basal lamina protein laminin, developed into the granulation tissue stroma from day 4 onward, being most abundant on days 5 and 6 and regressing thereafter. VEGFR-3-positive vessels were observed in the granulation tissue from day 5 onward. These vessels were distinct from the PAL-E/laminin/vWF-positive vessels and fewer in number, and they appeared to sprout from pre-existing VEGFR-3-positive lymphatic vessels at the wound edge. Unlike the blood vessels, very few VEGFR-3-positive lymphatic vessels persisted on day 9 and none on day 14. In chronic wounds such as ulcers and decubitus wounds of the lower extremity of humans, VEGFR-3 was also weakly expressed in the vascular endothelium. Our results suggest that transient lymphangiogenesis occurs in parallel with angiogenesis in healing wounds and that VEGFR-3 becomes up-regulated in blood vessel endothelium in chronic inflammatory wounds.

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Figures

Figure 1.
Figure 1.
Immunoperoxidase staining of serial sections of normal pig tissues. In pig ileum (A−D), VEGFR-3 stains vessels (arrowheads) that do not stain for the vascular endothelial marker PAL-E (arrows). The star (B) denotes the central artery of the villus. In pig lymphatic tissue of the tonsilla (E and F) and in the myocardium (G and H) the VEGFR-3-stained vessels (arrowheads) do not stain for vWF (arrows). In normal skin (I−L), VEGFR-3-positive vessels are negative for PAL-E and for smooth muscle actin and stain only very slightly for laminin (arrowheads, I−L), whereas PAL-E-, laminin-, and smooth muscle actin-positive blood vessels do not stain for VEGFR-3 (arrows, I−K). Scale bars, 100 μm (A, B, E−H), 200 μm (C and D), 300 μm (I−L).
Figure 2.
Figure 2.
Analysis of VEGFR-3-positive vessels and blood vessels in wound healing. The angiogenic vessels at the leading edge on day 4 stained with VEGFR-3 (A), PAL-E (B), laminin (C), or control antibodies (D). Granulation tissue on days 5, 7, 9, and 14 stained for VEGFR-3 (E−H) and PAL-E (I−L). Note that the VEGFR-3-positive vessels (arrowheads) do not stain for PAL-E (arrows) and vice versa. Sprouting of the VEGFR-3-positive vessel in granulation tissue of a day 7 punch biopsy wound stained for VEGFR-3 (M) and vWF (N). Note absence of VEGFR-3 on blood vessel endothelium (arrows) and the very slight staining of vWF in lymphatic endothelium. New lymphatic vessel (arrowheads) and blood vessel (arrows) sprouting from pre-existing vessels at the edge of a day 5 punch biopsy wound stained for VEGFR-3 (O) and PAL-E (P). The continuous line in O and P marks the wound edge. Scale bars, 50 μm (A−D, M, N) and 70 μm (E−L, O, P).
Figure 3.
Figure 3.
Vessels were counted on days 5, 6, 7, 9, and 14 in incisional wounds (PPI) and in punch biopsy wounds (PSI) from 4 to 7 square grids (area = 0.16 mm2) in a magnification field (40×), and the mean value score and SD were calculated. Only vessels with a lumen or consisting of more than a single endothelial cell were calculated. The granulation tissue did not develop into the wound area until day 4 to 5.
Figure 4.
Figure 4.
Immunoperoxidase staining of serial sections of a decubitus lesion (A−C), a diabetic leg ulcer (D−F), and a nondiabetic leg ulcer (G−I). Blood vessels (arrows) stain very weakly for VEGFR-3 (A, D, and G) and strongly for PAL-E (B, E, and H) and laminin (C, F, and I). Scale bars, 100 μm (A−F) and 200 μm (G−I).
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