The generation of new blood vessels (""""""""primary"""""""" angiogenesis) is a prominent feature of mammalian development in utero and continues for a time into post-natal life. Although angiogenesis is extremely limited in the normal adult, skin and most other adult tissues retain the capacity to initiate a brisk neovascular response to pathological stimuli. This """"""""secondary"""""""" angiogenesis is prominent in many skin disorders including tissue repair (wound healing), inflammation (e.g. psoriasis), and neoplasia. There is increasing evidence that the epidermis, not the dermis, is the source of vascular growth regulation; however, the precise regulatory mechanisms of skin angiogenesis remain poorly understood. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF) is a selective mitogen for vascular endothelial cells in vitro and induces microvascular hyperpermeability and angiogenesis in vivo. While VPF/VEGF has originally been identified and touted as a major tumor angiogenesis factor, we recently demonstrated striking overexpression of VPF/VEGF by epidermal keratinocytes and of VPF/VEGF receptors by papillary dermal microvessels in a variety of non- neoplastic skin disorders in which microvascular permeability and angiogenesis are prominent, including healing skin wounds and lesional psoriatic skin. Moreover, we found that VPF/VEGF is strikingly overexpressed by tumor cells in human squamous cell carcinomas of the skin, lesions that are characterized by and dependent on a richly angiogenic stroma. Taken together, our results suggest VPF/VEGF as a major factor regulating angiogenesis in the skin. To test this hypothesis, we successfully engineered transgenic mice transfected with sense or antisense VPF/VEGF cDNA under control of the keratin 14 promoter, thereby inducing selective overexpression or underexpression of VPF/VEGF in the skin with resulting vascular abnormalities. We now propose to study these mice in detail to evaluate the importance of VPF/VEGF in the primary skin angiogenesis of development and in the multistep process of skin carcinogenesis elicited by a chemical carcinogen-promoter combination (DMBA-TPA), applied to normal and VPF/VEGF transgenic mice. In addition, we will study the importance of transfected VPF/VEGF for the malignant growth and the tumor vascularization of human squamous cell carcinoma cell lines of varying malignancy, growing as xenografts in immunodeficient mice. Understanding the basic regulatory mechanisms of cutaneous angiogenesis is a prerequisite for the future development of new therapeutic approaches targeted at specific inhibition of angiogenesis in skin inflammation and skin cancer.
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