ENDOTHELIAL CELL DIVERSITY--MOLECULAR MECHANISMS AND PATHOLOGIC SIGNIFICANCE

人们普遍认为，内皮细胞在血管生成中起着关键作用。 心血管系统通过调节止血机制活动，血液 血管壁张力和营养运输。 很少有人意识到， 不同血管床的内皮细胞合成不同的基因 产品，从而能够执行器官特异性功能。 这 内皮细胞的表型多样性也可能参与 特定地区对不同疾病的易感性。 的 该部门开展的调查致力于阐明 内皮细胞异质性的分子基础及其在 动脉血栓形成的发展，特别是关于 心肌梗塞和脑血管中风。 我们已经证明，733 bp的5 '侧翼序列和第一外显子， 血管性血友病因子（VWF）基因的表达指导转基因 在小鼠脑内皮细胞，但不是其他血管床。 这些 数据表示组织特异性区域的第一定义， 内皮细胞限制性基因启动子。 虽然这个序列拥有 在所有内皮细胞中表达所需的信息中， 细胞，VWF基因的大片段应该提供额外的结构域 在其他血管床表达所需的。 我们打算描绘 这些区域通过体外和转基因研究的组合， 并分离/分子克隆关键调节因子。 是我们 期望这项工作将揭示基因表达如何在不同的 血管床被控制，从而开始确定分子基础 内皮细胞的多样性。 我们还将利用VWF的部分 基因启动子，其仅指导脑内皮细胞中的表达， 设计新的血栓性中风和脑出血动物模型 由纤维蛋白溶解剂引起。 我们已经证明，733 bp的5 '侧翼序列和第一外显子， 血管性血友病因子（VWF）基因的表达指导转基因 在小鼠脑内皮细胞，但不是其他血管床。 这些 数据表示组织特异性区域的第一定义， 内皮细胞限制性基因启动子。 虽然这个序列拥有 在所有内皮细胞中表达所需的信息中， 细胞中，更大的片段的VWF基因应该提供额外的结构域 在其他血管床表达所需的。 我们打算描绘 这些区域通过体外和转基因研究的组合， 并分离/分子克隆关键调节因子。 是我们 期望这项工作将揭示基因表达如何在不同的 血管床被控制，从而开始确定分子基础 内皮细胞的多样性。 我们还将利用VWF的部分 基因启动子，其仅指导脑内皮细胞中的表达， 设计新的血栓性中风和脑出血动物模型 由纤维蛋白溶解剂引起。

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.