Metabolic Regulation of Muscle Blood Flow

流向外周循环的血液被调节，以维持营养物质的输送和组织的代谢需求之间的平衡。血液流向新陈代谢活跃的组织。这种血流量的增加是由于末梢小动脉和更大的上游血管的小动脉直径增加的结果。末梢小动脉似乎决定了血流的分布，而上游或“供血”血管在调节组织总血流方面更为重要。随着新陈代谢的增加，血管活性代谢物从组织中释放出来。虽然已知血管活性代谢物影响末梢小动脉的直径，但代谢因素调节上游小动脉直径的机制尚不清楚。我们实验室和其他实验室最近的研究表明，血管活性物质的小静脉-小动脉扩散具有重要作用。本提案中概述的研究将检验以下工作假设。作为对血流和组织代谢不匹配的反应，静脉内皮细胞直接或间接地感受到PO2的降低和/或PCO2和H+的增加，导致调节相邻小动脉张力的花生四烯酸的血管活性代谢产物的释放。拟议的研究将利用最近开发的原位微循环技术来验证这一假说，在这种技术中，我们能够选择性地去除静脉内皮细胞，并评估其对血流调节的影响。拟议的研究将检验两个具体的假设：1)静脉内皮细胞释放花生四烯酸的代谢物，该代谢物从小静脉扩散到小动脉，导致小动脉扩张，以响应组织代谢率的增加。2)静脉内皮细胞直接或间接地对缺氧、高碳酸血症和酸中毒作出反应，以启动一种或多种血管活性因子从静脉内皮细胞释放。这些研究将为我们理解血管内皮细胞衍生因子在血流调节中的静脉-小动脉扩散的重要性提供新的重要信息。

The blood flow to the peripheral circulation is regulated to maintain a balance between the delivery of nutrients and the metabolic demands of the tissue. Blood flow increases to a metabolically active tissue. This increased blood flow is the result of an increase in arteriolar diameter of terminal arterioles and larger upstream vessels. The terminal arterioles appear to determine distribution of flow while the upstream or "feed" vessels are more important in regulating total tissue flow. With an increase in metabolism there is the release of vasoactive metabolites from the tissue. Although vasoactive metabolites are known to affect the diameters of terminal arterioles the mechanisms by which metabolic factors regulate the diameter of upstream arterioles is uncertain. Recent studies from our lab and others have indicated an important role for the venular-arteriolar diffusion of vasoactive substances. The studies outlined in this proposal will test the following working hypothesis. In response to mismatches in blood flow and tissue metabolism, decreases in PO2 and/or increases in PCO2 and H+ are directly or indirectly sensed by the venular endothelial cells, resulting in the release of vasoactive metabolites of arachidonic acid which regulate the tone of adjacent arterioles. The proposed studies will test this hypothesis utilizing recently developed in situ microcirculatory techniques in which we are able to selectively remove the venular endothelium and assess the impact on blood flow regulation. The proposed studies will test two specific hypotheses: 1) The venular endothelium releases a metabolite of arachidonic acid that diffuses from the venule to the arteriole to cause an arteriolar dilation in response to an increase in tissue metabolic rate. 2) The venular endothelium responds to hypoxia, hypercapnia, and acidosis, directly, or indirectly to initiate the release of one or more vasoactive factors from the venular endothelial cells. These studies should provide new and important information relevant to our understanding the importance of venular-arteriolar diffusion of endothelial derived factors in the regulation of blood flow.