Relaxin in Systemic Vascular Mechanisms and Function

描述（由申请人提供）：血管僵硬作为一个独立的心血管危险因素越来越重要，特别是在心血管疾病中，如与加速衰老和慢性高血压相关的疾病。虽然传统上与女性生殖过程有关，但松弛素（Rlx）正在成为心血管功能的重要调节剂。当给药于未怀孕的雌性和雄性大鼠时，Rlx降低全身血管阻力，增加心输出量和全身动脉顺应性，以及离体肾小动脉的顺应性。初步研究表明，在离体大鼠（包括雄性和雌性）动脉中有松弛素mRNA和蛋白表达，在培养的人血管细胞中有松弛素和松弛素受体mRNA表达。其他初步研究表明，从松弛素缺乏小鼠中分离的小肾动脉具有顺应性降低和肌原性反应性增加的特点。因此，本项目拟检验Rlx是否也是一种血管源性的、局部作用的顺应和放松因子，而不考虑性别。我们假设在松弛素缺乏的小鼠中，稳定和搏动的动脉负荷增加，并且分离的血管不太适应，并且以胶原蛋白水平较高为特征。稳定和脉动的动脉负荷将确定使用主动脉压力流量测量在有意识的老鼠。野生型和基因敲除小鼠离体动脉的被动力学将使用等压动脉造影进行评估。将进行生化分析以量化血管胶原的特征（例如，数量、多肽链、交联）。该项目的结果可以确定松弛素在治疗或预防某些已知发生血管僵硬增加和血管收缩的心血管疾病中的可能的治疗应用。

DESCRIPTION (provided by applicant): Vascular stiffness is gaining more importance as an independent cardiovascular risk factor especially, in cardiovascular pathologies such as those associated with accelerated aging and chronic hypertension. Although traditionally associated with female reproductive processes, relaxin (Rlx) is emerging as an important modulator of cardiovascular function. When administered to non-pregnant female and male rats, Rlx decreases systemic vascular resistance, and increases cardiac output and global arterial compliance, as well as the compliance of small renal arteries ex vivo. Preliminary studies have shown relaxin mRNA and protein expression in isolated arteries from rats (both male and female) and relaxin and relaxin receptor mRNA expression in cultured human vascular cells. Other preliminary studies have shown that small renal arteries isolated from relaxin deficient mice are characterized by reduced compliance, and increased myogenic reactivity. Therefore, this project proposes to test whether Rlx, irrespective of gender, is also a vascular-derived, locally acting compliance and relaxing factor. We hypothesize that the steady and pulsatile arterial loads are increased, and isolated blood vessels are less compliant and characterized by higher levels of collagen in relaxin deficient mice. Steady and pulsatile arterial loads will be determined using aortic pressure flow measurements in conscious mice. Passive mechanics of isolated arteries from wild type and knockout mice will be assessed using an isobaric pressure arteriograph. Biochemical analyses will be performed to quantify vascular collagen characteristics (e.g., amount, polypeptide chains, crosslinks). Results of this project could identify possible therapeutic applications of relaxin in treating or preventing certain cardiovascular pathologies wherein increased vascular stiffness and vasoconstriction are known to occur.