Relaxin in Systemic Vascular Mechanisms and Function

描述（由申请方提供）：血管僵硬作为一种独立的心血管风险因素越来越重要，尤其是在心血管病理学中，例如与加速老化和慢性高血压相关的疾病。尽管传统上与女性生殖过程相关，但松弛素（Rlx）正在成为心血管功能的重要调节剂。当给予非妊娠雌性和雄性大鼠时，Rlx降低全身血管阻力，并增加心输出量和总体动脉顺应性，以及离体小肾动脉的顺应性。初步研究表明，松弛素mRNA和蛋白质表达在离体动脉大鼠（男性和女性）和松弛素和松弛素受体mRNA表达在培养的人血管细胞。其他初步研究表明，从松弛素缺乏小鼠中分离的小肾动脉的特征在于顺应性降低和肌源性反应性增加。因此，本项目拟测试Rlx（不考虑性别）是否也是血管源性、局部作用的顺应性和松弛因子。我们假设，在松弛素缺乏的小鼠中，稳定和脉动动脉负荷增加，并且离体血管的顺应性较低，并且其特征在于胶原蛋白水平较高。将使用清醒小鼠中的主动脉压力流量测量来确定稳定和脉动动脉负荷。将使用等压动脉造影术评估来自野生型和基因敲除小鼠的分离动脉的被动力学。将进行生化分析以量化血管胶原特性（例如，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心血管疾病中的可能治疗应用，其中已知会发生血管僵硬和血管收缩增加。

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.