Endogenous Relaxin Regulates Vascular Function in Nonpregnant Females and Males

内源性松弛素调节非妊娠女性和男性的血管功能

• 批准号: 7388841
• 负责人: Kirk P Conrad
• 金额: $ 33.99万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-20 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388841
• 关键词: Affect; Affinity; Age; Age-Months; Aging; Animals; Antibodies; Aortic Aneurysm; Appendix; Applications Grants; Arteries; Big Endothelin; Binding; Biological Assay; Blood Circulation; Blood Vessels; Cardiac; Cardiac Output; Cardiovascular Physiology; Cardiovascular system; Cells; Characteristics; Complex; Conscious; Constriction procedure; Coupling; Data; Detection; Dissection; Distal; Engineering; Female; Fibrosis; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Gelatinases; Gender; Genes; Hormone Receptor; Hormones; Human; Hypertension; Immunohistochemistry; In Situ Hybridization; Kidney; Knock-out; Knowledge; Left; Leucine-Rich Repeat; Ligands; Localized; Lung; Measurement; Mechanics; Mediating; Mesentery; Messenger RNA; Modeling; Molecular; Mus; Organ; Osmolalities; Pathology; Peripheral; Peripheral Resistance; Plasma; Polymerase Chain Reaction; Pregnancy; Progress Reports; Proteins; Rattus; Relaxation; Relaxin; Renal Circulation; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Smooth Muscle; Smooth Muscle Myocytes; Soluble Guanylate Cyclase; System; Terminology; Testing; Tissues; Tube; Vascular Endothelium; Vascular resistance; Vasodilation; Ventricular; Wild Type Mouse; base; concept; corpus luteum; design; electric impedance; hemodynamics; indexing; instrument; kidney vascular structure; mRNA Expression; male; novel; pressure; protein expression; receptor; receptor binding; receptor expression; relaxin receptor; renal artery; reproductive; reproductive function; wasting

DESCRIPTION (provided by applicant): Although traditionally associated with function of reproductive organs during pregnancy, relaxin (Rlx) is emerging as an important player in vascular function. We previously showed that circulating Rlx whether endogenously released during pregnancy or exogenously adminstered to conscious, nonpregnant female and male rats induces systemic and renal vasodilation, and increases arterial compliance. Here, we propose to explore two overarching concepts: (1) endogenous Rlx regulates vascular function in nonpregnant females and males, and (2) there is a local, vascular-derived Rlx hormone/receptor system. These concepts are supported by preliminary molecular analyses showing Rlx and Rlx receptor expression by isolated rodent arteries and cultured human vascular cells, as well as by functional studies demonstrating reduced compliance and increased myogenic reactivity of arteries isolated from nonpregnant female and male mice deficient in the M1 relaxin gene. We have designed five Hypotheses and Specific Aims to test these two overarching concepts. In Aims 1 and 2, we propose to corroborate and extend our preliminary studies by further characterizing the expression of relaxins and relaxin receptors in vascular tissues from mice and humans. In Aims 3-5, we propose to investigate steady and pulsatile systemic arterial loads, and renal hemodynamics in conscious and unrestrained, chronically instrumented wild-type and Rlx-deficient mice, as well as myogenic reactivity and passive mechanics of arteries isolated from these animals. These studies will utilize nonpregnant female and male mice, as well as both young and older animals, thereby exploring gender and age interactions. To our knowledge, the concepts of endogenous Rlx mediating vascular relaxation and increased compliance in nonpregnant females and males, and of a local, vascular-derived Rlx hormone/receptor system are novel. If they are validated, then abnormalities in endogenous Rlx or its receptor may contribute to various vascular pathologies, e.g., a deficiency might contribute to increased arterial constriction and stiffness associated with hypertension and aging (both normal and accelerated), and an excess might contribute to aortic aneurysm formation and dissection. Thus, the influence of endogenous Rlx on vascular function is likely to be a general phenomenon, and not one limited exclusively to pregnancy.

描述（由申请人提供）：虽然传统上松弛素 (Rlx) 与怀孕期间生殖器官的功能相关，但它正在成为血管功能的重要参与者。我们之前表明，循环 Rlx 无论是在怀孕期间内源性释放还是外源性给予有意识的非怀孕雌性和雄性大鼠，都会诱导全身和肾血管舒张，并增加动脉顺应性。在这里，我们建议探索两个总体概念：（1）内源性 Rlx 调节非妊娠女性和男性的血管功能，（2）存在局部血管源性 Rlx 激素/受体系统。这些概念得到了初步分子分析的支持，初步分子分析显示了分离的啮齿动物动脉和培养的人类血管细胞表达 Rlx 和 Rlx 受体，功能研究也证明从缺乏 M1 松弛素基因的非怀孕雌性和雄性小鼠中分离的动脉的顺应性降低和肌源性反应性增加。我们设计了五个假设和具体目标来测试这两个总体概念。在目标 1 和 2 中，我们建议通过进一步表征小鼠和人类血管组织中松弛素和松弛素受体的表达来证实和扩展我们的初步研究。在目标 3-5 中，我们建议研究清醒和不受限制、长期仪器化的野生型和 Rlx 缺陷小鼠的稳定和脉动全身动脉负荷和肾血流动力学，以及从这些动物中分离出的动脉的肌源性反应性和被动力学。这些研究将利用未怀孕的雌性和雄性小鼠，以及年轻和年老的动物，从而探索性别和年龄的相互作用。据我们所知，内源性 Rlx 介导非怀孕女性和男性血管松弛和增加顺应性，以及局部血管衍生的 Rlx 激素/受体系统的概念是新颖的。如果它们得到验证，那么内源性 Rlx 或其受体的异常可能会导致各种血管病变，例如，缺乏可能会导致与高血压和衰老（正常和加速）相关的动脉收缩和僵硬增加，而过量可能会导致主动脉瘤形成和夹层。因此，内源性 Rlx 对血管功能的影响可能是一种普遍现象，而不仅仅限于妊娠。