VEGF VPF OVEREXPRESSION IN SKIN OF TRANSGENIC MICE INDUCES ANGIOGENESIS, VASCULAR HYPERPERMEABILITY AND ACCELERATED TUMOR-DEVELOPMENT/

Upregulation of keratinocyte-derived VEGF-A expression has recently be en established in non-neoplastic processes of skin such as wound heali ng, blistering diseases and psoriasis, as well as in skin neoplasia, T o further characterize the effects of VEGF-A in skin in vivo, we have developed transgenic mice expressing the mouse VEGF(120) under the con trol of a 2,4 kb 5' fragment of keratin K6 gene regulatory sequences t hat confers transgene inducibility upon hyperproliferative stimuli. As expected from the inducible nature of the transgene, two of the three founder mice obtained (V27 and V208), showed no apparent phenotype, H owever, one founder (V2), mosaic for transgene integration, developed scattered red spots throughout the skin at birth, The transgenic offsp ring derived from this founder developed a striking phenotype characte rized by swelling and erythema, resulting in early postnatal lethality . Histological examination of the skin of these transgenics demonstrat ed highly increased vascularization and edema leading to disruption of skin architecture. Expression of the transgene was silent in adult an imals of lines derived from founders V27 and V208, Phorbol ester-induc ed hyperplasia resulted in transgene induction and increased cutaneous vascularization in adult transgenic mice of these lines. Skin carcino genesis experiments performed on hemizygous crosses of V208 mice with activated H-ras-carrying transgenic mice (TG.AC) resulted in accelerat ed papilloma development and increased tumor burden. Previous results from our laboratory showed that VEGF upregulation is a major angiogeni c stimulus in mouse epidermal carcinogenesis. By overexpressing VEGF i n the skin of transgenic mice we now move a step further toward showin g that VEGF mediated angiogenesis is a rate-limiting step in the genes is of premalignant lesions, such as mouse skin papilloma, Our transgen ic mice constitute an interesting :model system for in vivo study of t he cutaneous angiogenic process and its relevance in tumorigenesis and other skin diseases.