It is widely recognized that endothelial cells play a critical role int he cardiovascular system by regulating hemostatic mechanism activity, blood vessel wall tone, and nutrient traffic. It is less often appreciated that endothelial cells of different vascular beds synthesize diverse set of gene products and are thereby able to carry out organ specific functions. This phenotypic diversity of endothelial cells may also be involved in the susceptibility of particular regions to different diseases. The investigations carried out by this component are devoted to elucidating the molecular basis of endothelial cell heterogeneity and its potential role in the development of arterial thrombosis particularly with regard to myocardial infarction and cerebrovascular stroke. We have demonstrated that 733 bp of the 5' flanking sequence and first exon of the von Willebrand factor (VWF) gene directs expression of a transgene in mice to brain endothelial cells, but not other vascular beds. These data represent the first definition of tissue specific regions of an endothelial cell restricted gene promoter. While this sequence possess only part of the information necessary for expression in all endothelial cells, large segments of the VWF gene should provide additional domains required for expression in other vascular beds. We intend to delineate these regions by a combination of in vitro as well as transgenic studies, and isolate/molecularly clone the critical regulatory factors. It is our expectation that this work will reveal how gene expression in different vascular beds is controlled and thereby begin to define the molecular basis of endothelial cell diversity. We will also utilize the portion of the VWF gene promoter which directs expression only in brain endothelial cells to devise novel animal models of thrombotic stroke and brain hemorrhage induced by fibrinolytic agents. We have demonstrated that 733 bp of the 5' flanking sequence and first exon of the von Willebrand factor (VWF) gene directs expression of a transgene in mice to brain endothelial cells, but not other vascular beds. These data represent the first definition of tissue specific regions of an endothelial cell restricted gene promoter. While this sequence possesses only part of the information necessary for expression in all endothelial cells, larger segments of athe VWF gene should provide additional domains required for expression in other vascular beds. We intend to delineate these regions by a combination of in vitro as well as transgenic studies, and isolate/molecularly clone the critical regulatory factors. It is our expectation that this work will reveal how gene expression in different vascular beds is controlled and thereby begin to define the molecular basis of endothelial cell diversity. We will also utilize the portion of the VWF gene promoter which directs expression only in brain endothelial cells to devise novel animal models of thrombotic stroke and brain hemorrhage induced by fibrinolytic agents.
Showing the most recent 10 out of 217 publications
