Studies of the structural and functional characteristics of endothelial cells in vivo and in vitro have established that the vascular endothelium is made up of a phenotypically diverse group of cells. The observations that endothelial cells of different vascular beds express specific sets of genes that carry out organ- or tissue-specific functions has reinforced the concept of organ/tissue specific endothelial cell heterogeneity. However, studies in the applicant's laboratory on the expression of endothelial cell proteins during fetal development indicate that endothelial cell gene expression also differs among vessel types and developmental stages even within the same vascular bed. Using tissue plasminogen activator (tPA) expression as an endothelial cell marker, we have found a pattern of progressive and transitory tPA expression in endothelial cells of specific arteries. Expression of tPA starts with the dorsal aortae and is followed by the appearance of tPA in the endothelium of the subclavian, vertebral, and main pulmonary arteries and eventually most of the arteries of the brain. Blood vessels of other organs do not express tPA nor has it ever been observed in veins or capillary endothelium. By birth endothelial cell tPA expression is localized exclusively in the superficial arteries and arterioles of the central nervous system and the pulmonary arteries within the lung parenchyma. None of the arteries of the thoracic cavity continue to express tPA. Thus, sequential expression of tPA antigen occurs in a select group of arteries as they develop and mature in what appears to be a a developmentally regulated fashion. This dynamic pattern of tPA expression has led to our proposal that during development, tPA production in arterial endothelial cells is regulated by environmental factors within and around these blood vessels. The hypothesis to be tested is that tPA expression in specific arterial endothelial cells is controlled by a set of transcriptional regulatory elements and factors that are """"""""activated"""""""" in response to the conditions within the developing fetal arterial system. This proposal will identify the arterial endothelial cell specific DNA promoter sequences and transcription factors that mediate developmental tPA expression in the central nervous system and test the functional relevance of these components in cultured endothelial cells and transgenic mouse lines. This proposal will address the question of the molecular mechanism by which endothelial cell gene expression is limited to specific subsets of cells during development. This will not only serve to broaden our understanding of the molecular basis of endothelial phenotype variation but will also serve as a model for other developing systems.
| Pham, Nhat-Long; Franzen, Amy; Levin, Eugene G (2004) NF1 regulatory element functions as a repressor of tissue plasminogen activator expression. Arterioscler Thromb Vasc Biol 24:982-7 |
| Ding, Lan; Donate, Fernando; Parry, Graham C N et al. (2002) Inhibition of cell migration and angiogenesis by the amino-terminal fragment of 24kD basic fibroblast growth factor. J Biol Chem 277:31056-61 |
| Levin, E G; Banka, C L; Parry, G C (2000) Progressive and transient expression of tissue plasminogen activator during fetal development. Arterioscler Thromb Vasc Biol 20:1668-74 |
| Piotrowicz, R S; Maher, P A; Levin, E G (1999) Dual activities of 22-24 kDA basic fibroblast growth factor: inhibition of migration and stimulation of proliferation. J Cell Physiol 178:144-53 |
