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正变得越来越重要，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。尽管松弛素(RLX)传统上与女性生殖过程有关，但它正在成为心血管功能的重要调节剂。在非妊娠雌性和雄性大鼠中，RLX降低全身血管阻力，增加心输出量和整体动脉顺应性，以及体外小肾动脉顺应性。初步研究表明，松弛素在大鼠(雌雄)分离的动脉中均有表达，在培养的人血管细胞中也有松弛素及松弛素受体的表达。其他初步研究表明，从松弛蛋白缺乏的小鼠分离的小肾动脉的特征是顺应性降低，肌源性反应性增强。因此，该项目建议测试RLX是否也是一种血管衍生的局部作用的顺应性和松弛因子，而不分性别。我们假设，在松弛素缺乏的小鼠中，稳定的和搏动的动脉负荷增加，分离的血管顺应性较差，以胶原水平较高为特征。使用清醒小鼠的主动脉压力流量测量将确定稳定和脉动的动脉负荷。来自野生型和基因敲除小鼠的分离动脉的被动力学将使用等压动脉造影仪进行评估。将进行生化分析以量化血管胶原蛋白的特征(例如，数量、多肽链、交联物)。这一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方面的可能治疗应用，在这些疾病中，已知会发生血管僵硬和血管收缩。

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.