Physiological Basis of Vascular Contractility

描述（由申请人提供）： 流体动力是动脉、静脉和淋巴管收缩功能的重要内在调节因子。 所有3种血管类型都对跨壁压和管腔切应力的变化做出反应，但它们的反应差异很大。 对压力升高的反应是，小动脉表现出强烈的、持续的收缩;小静脉表现出短暂的、弱的收缩;动脉收缩增加了它们的阶段性收缩速率，张力几乎没有变化或没有变化。 剪切应力抑制所有三个血管的压力诱导的反应。 此外，根据主要的姿势流体静力梯度，每种血管类型的收缩反应在身体的不同区域是可变的。 该提议的中心假设是血管间和区域间的血管跨壁压差异显著影响平滑肌（SM）收缩蛋白表达和功能的异质性。 为了验证这一假设，我们将确定跨壁压在多大程度上决定了血管功能、机械性能和蛋白质表达的异质性。 每个目标将利用从大鼠4个不同区域环境（腿、颈、胸、腹部）分离的相邻小动脉、小静脉和血管，其中血管跨壁压梯度不同。 方法包括使用具有受控压力/流量的分离/插管血管，力反馈控制下的钢丝肌电描记器上的血管段，mRNA、蛋白质和肌球蛋白ATP酶分析，免疫荧光共聚焦显微镜。 在每个位置的每种血管类型中，我们的目的是比较：1）相对于血管壁的被动机械特性，对压力和剪切应力的功能性收缩反应; 2）血管SM的主动长度-张力和力-速度关系; 3）相对于肌球蛋白ATP酶活性的SM收缩和调节蛋白亚型的表达。 将对结果进行整合，以更全面地了解这些血管中血管SM之间的相似性和差异。我们预测血管力学和功能的血管间和区域间差异将反映SM收缩蛋白亚型表达的潜在差异。 此外，预测的功能行为的小动脉，小静脉和动脉，以反映其各自的跨壁压梯度的大小。 这些比较以前没有做过，将大大促进我们对血管收缩功能异质性基础的理解。

DESCRIPTION (provided by applicant): Hydrodynamic forces are important intrinsic regulators of contractile function for arterial, venous and lymphatic vessels. All 3 vessel types react to changes in transmural pressure and luminal shear stress, but their responses differ dramatically. In response to pressure elevation, arterioles exhibit strong, sustained constrictions; venules transient, weak constrictions; lymphatics increase their rate of phasic contractions, with little or no change in tone. Shear stress inhibits the pressure-induced responses of all three vessels. Additionally, the contractile responses for each vessel type are variable across different regions of the body, according to the prevailing postural hydrostatic gradients. The central hypothesis of this proposal is that inter-vessel and inter-regional differences in vascular transmural pressure significantly influence the heterogeneity of smooth muscle (SM) contractile protein expression and function. To test this hypothesis, we will determine the extent to which the heterogeneity of vessel function, mechanical properties, and protein expression are determined by transmural pressure. Each aim will utilize adjacent arterioles, venules and lymphatics isolated from 4 different regional environments (leg, neck, thorax, abdomen) of the rat in which the vascular transmural pressure gradients vary. Methods include using isolated/cannulated vessels with controlled pressure/flow, vessel segments on wire myographs under force-feedback control, mRNA, protein and myosin ATPase analyses, immunofluorescence confocal microscopy. In each vessel type at each location our aims are to compare: 1) the functional contractile responses to pressure and shear stress relative to the passive mechanical properties of the vessel wall; 2) active length-tension and force-velocity relationships of vascular SM; 3) expression of SM contractile and regulatory protein isoforms relative to myosin ATPase activity. The results will be integrated to obtain a more complete picture of the similarities and differences between vascular SM in these vessels. We predict that inter-vessel and inter-regional differences in vascular mechanics and function will reflect underlying differences in the expression of SM contractile protein isoforms. In addition, the functional behaviors of arterioles, venules and lymphatics are predicted to reflect the magnitudes of their respective transmural pressure gradients. These comparisons have not been made before and will significantly advance our understanding of the basis for the heterogeneity in vascular contractile function.