ENDOTHELIAL CELL DIVERSITY--MOLECULAR MECHANISMS AND PATHOLOGIC SIGNIFICANCE

人们普遍认为血管内皮细胞在血管内皮细胞损伤中起着关键作用。 心血管系统通过调节止血机制活动、血液 血管壁色调和营养流量。但很少有人意识到 不同血管床的内皮细胞合成不同的一套基因 产品，并因此能够执行器官特定的功能。这 内皮细胞的表型多样性也可能参与了 特定地区对不同疾病的易感性。这个 该部门进行的调查致力于阐明 内皮细胞异质性的分子基础及其在血管内皮细胞异质性中的作用 动脉血栓形成的发展，特别是与 心肌梗死和脑血管病。 我们已经证明了5‘侧翼序列和第一外显子的733bp Von Willebrand因子(Vwf)基因控制转基因的表达 在小鼠脑内皮细胞，而不是其他血管床。这些 数据表示组织特定区域的第一个定义 内皮细胞限制性基因启动子。虽然这个序列拥有 仅在所有内皮细胞中表达所需的部分信息 细胞，VWF基因的大片段应该提供额外的结构域 在其他血管床中表达所必需的。我们打算描绘出 这些区域通过体外研究和转基因研究相结合， 并分离/分子克隆关键调控因子。这是我们的 期望这项工作将揭示不同的基因表达 血管床被控制，从而开始定义分子基础 内皮细胞的多样性。我们还将利用VWF的部分 仅在脑内皮细胞中引导表达的基因启动子 设计新的血栓性中风和脑出血动物模型 由纤溶剂诱导。 我们已经证明了5‘侧翼序列和第一外显子的733bp Von Willebrand因子(Vwf)基因控制转基因的表达 在小鼠脑内皮细胞，而不是其他血管床。这些 数据表示组织特定区域的第一个定义 内皮细胞限制性基因启动子。而这个序列拥有 仅在所有内皮细胞中表达所需的部分信息 细胞，VWF基因的较大片段应该提供额外的结构域 在其他血管床中表达所必需的。我们打算描绘出 这些区域通过体外研究和转基因研究相结合， 并分离/分子克隆关键调控因子。这是我们的 期望这项工作将揭示不同的基因表达 血管床被控制，从而开始定义分子基础 内皮细胞的多样性。我们还将利用VWF的部分 仅在脑内皮细胞中引导表达的基因启动子 设计新的血栓性中风和脑出血动物模型 由纤溶剂诱导。

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.