Figure 4.
Figure 4. Lymphatic vessel enlargement and proliferation in the ear skin of VEGF-A transgenic mice. In VEGF-A transgenic mice, the number of small, tortuous, CD31+(red)/LYVE-1– blood vessels was increased in the superficial dermis adjacent to the site of transgenic VEGF-A overexpression (C-D, G-H), as compared with wild-type mice (A-B, E-F). Lymphatic vessels (LYVE-1+, green) were larger in the ear skin of VEGF-A–overexpressing mice (C, G) than in wild-type mice (A, E) under noninflamed conditions. At 24 hours after elicitation of DTH reactions, lymphatic vessels were dramatically more enlarged in transgenic mice (D) compared with wild-type littermates (B). By 30 days later, lymphatic vessels in challenged ears had returned to normal size in wild-type mice (F), but not in VEGF-A transgenic mice, in which lymphatic vessels remained enlarged (H). Scale bar: 100 μm. Double stains for the lymphatic marker podoplanin (green) and the proliferation marker Ki67 (red) demonstrated active lymphatic endothelial cell proliferation (arrowheads) in the enlarged lymphatics of inflamed ears (14 days) of VEGF-A transgenic mice (J) but not in vehicle-treated ears (I). Scale bar: 50 μm. Computer-assisted morphometric analysis revealed comparable numbers of lymphatic vessels per millimeter ear length in VEGF-A transgenic (TG) and wild-type mice, either treated with vehicle (□) or after induction of the DTH (▪) (K). In contrast, the size of lymphatic vessels was significantly increased in untreated skin of VEGF-A transgenic mice with a further pronounced increase at 24 hours after challenge (L). After 30 days, the number of lymphatic vessels per millimeter ear length varied only insignificantly between transgenic and wild-type mice (M). However, lymphatic vessels remained enlarged in transgenic mice, but had returned to their original size in wild-type mice (N). Data are expressed as mean plus or minus SEM (n = 3 per genotype and time point). **P < .01, ***P < .001. In contrast, the lymphatic vessel size in the inflamed ear skin of PlGF transgenic mice (O) and of TSP-2–deficient mice (P), which are also characterized by enhanced inflammation, angiogenesis, and edema formation, was comparable to wild-type mice at 24 hours after induction of DTH reactions (n = 3 per genotype and time point).

Lymphatic vessel enlargement and proliferation in the ear skin of VEGF-A transgenic mice. In VEGF-A transgenic mice, the number of small, tortuous, CD31+(red)/LYVE-1– blood vessels was increased in the superficial dermis adjacent to the site of transgenic VEGF-A overexpression (C-D, G-H), as compared with wild-type mice (A-B, E-F). Lymphatic vessels (LYVE-1+, green) were larger in the ear skin of VEGF-A–overexpressing mice (C, G) than in wild-type mice (A, E) under noninflamed conditions. At 24 hours after elicitation of DTH reactions, lymphatic vessels were dramatically more enlarged in transgenic mice (D) compared with wild-type littermates (B). By 30 days later, lymphatic vessels in challenged ears had returned to normal size in wild-type mice (F), but not in VEGF-A transgenic mice, in which lymphatic vessels remained enlarged (H). Scale bar: 100 μm. Double stains for the lymphatic marker podoplanin (green) and the proliferation marker Ki67 (red) demonstrated active lymphatic endothelial cell proliferation (arrowheads) in the enlarged lymphatics of inflamed ears (14 days) of VEGF-A transgenic mice (J) but not in vehicle-treated ears (I). Scale bar: 50 μm. Computer-assisted morphometric analysis revealed comparable numbers of lymphatic vessels per millimeter ear length in VEGF-A transgenic (TG) and wild-type mice, either treated with vehicle (□) or after induction of the DTH (▪) (K). In contrast, the size of lymphatic vessels was significantly increased in untreated skin of VEGF-A transgenic mice with a further pronounced increase at 24 hours after challenge (L). After 30 days, the number of lymphatic vessels per millimeter ear length varied only insignificantly between transgenic and wild-type mice (M). However, lymphatic vessels remained enlarged in transgenic mice, but had returned to their original size in wild-type mice (N). Data are expressed as mean plus or minus SEM (n = 3 per genotype and time point). **P < .01, ***P < .001. In contrast, the lymphatic vessel size in the inflamed ear skin of PlGF transgenic mice (O) and of TSP-2–deficient mice (P), which are also characterized by enhanced inflammation, angiogenesis, and edema formation, was comparable to wild-type mice at 24 hours after induction of DTH reactions (n = 3 per genotype and time point).

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