阻力血管的钠尿肽敏感性降低促发高血压及其机制

As an cardiovascular disease with very high incidence rate, hypertension threatens the human health seriously. The normal blood pressure is sustained mainly depending on the resistance by micro or small arteries. Our latest preliminary experiments indicated that the sensitivity of mesenteric small arteries to natriuretic peptides (NPs) decreased before the hypertension formed, which highlights predisposition to hypertension by reduced sensitivity of resistance blood vessel to NPs. In addition, our previous work indicated that enhanced vasoconstriction and proliferation was alleviated by NPs (PLoS One, 2011; Physiol Res, 2010). It suggests that "the imbalance between NPs and adrenergic receptor (AR) signals" caused by reduced vascular sensitivity to NPs might result in hypertension, and might participate in the hypertensive vascular remodeling. However, the underlying mechanisms remain largely unknown. On the basis of our previous work, the current study is to investigate the changes of vascular sensitivity to NPs during the genesis and development of hypertension. Moreover, the mice with conditionally knocked out natriuretic peptide receptor A (NPRA) or PKG in vascular smooth muscles are to be used to investigate the effects of "the imbalance between NPs and AR signals" on the tone and structure of blood vessels. The present study is supposed to find a novel mechanism that decreased sensitivity of resistance blood vessels to NPs is culpable of the disease of hypertension. Also, this project will give clues of efficient methods and targets against hypertension by the means of improving the vascular sensitivity to NPs.

作为发病率最高的心血管疾病，高血压严重威胁人类健康。正常血压的维持主要取决于微（小）动脉对血流产生的阻力。申请者预实验表明，自发性高血压大鼠（SHR）在血压升高之前肠系膜微动脉的钠尿肽敏感性已降低，提示阻力血管的钠尿肽敏感性降低可能促发高血压。我们的前期结果还表明，钠尿肽可抑制α1-肾上腺素能受体（AR）引起的血管收缩和血管平滑肌细胞增殖（PLoS One, 2011; Physiol Res, 2010），提示阻力血管钠尿肽敏感性降低导致的"钠尿肽-AR信号失衡"可能促发高血压以及血管重构，但其具体机制尚不清楚。本课题拟研究SHR阻力血管钠尿肽敏感性的变化规律，并拟采用血管平滑肌条件敲除钠尿肽A受体（NPRA）或PKG的小鼠，探讨"钠尿肽-AR信号失衡"对血管紧张性、血压和血管结构的影响，旨在揭示阻力血管的钠尿肽敏感性降低促发高血压的全新机制，并为防治高血压提供新思路。

作为发病率最高的心血管疾病，高血压严重威胁人类健康。阐明高血压发生和发展的病理生理学机制，进而以此为切入点采取有效的预防和治疗措施，具有重要的现实意义。正常血压的维持主要取决于微（小）动脉对血流产生的阻力。我们以往的研究和文献报道显示，阻力血管钠尿肽敏感性降低导致的“钠尿肽-AR信号失衡”可能促发高血压以及血管重构，但其具体机制尚不清楚。本课题以年龄-性别匹配的正常血压WKY（Wistar-Kyoto）大鼠为对照，比较研究了自发性高血压大鼠（spontaneously hypertensive rat，SHR）在高血压发生、发展的过程中阻力血管钠尿肽敏感性的变化规律和机制，“NPRA-cGMP-PKG与α1-AR-PKC信号失衡”对血管张力和结构的影响，以及有氧运动训练的作用。发现：与WKY大鼠相比较，幼年（4周龄）SHR肠系膜动脉对ANP的血管舒张反应明显降低，成年（16周龄）SHR肠系膜动脉对ANP的血管舒张反应进一步降低。相应的，幼年（4周龄）SHR血浆cGMP/ANP比值已经显著降低，而在成年（16周龄）SHR的cGMP/ANP比值进一步降低，提示，ANP升高cGMP的功能受损，而ANP抵抗发生在高血压之前的情形表明，钠尿肽抵抗促发高血压。与WKY大鼠相比较，磷酸二酯酶PDE5在幼年与成年的SHR肠系膜动脉的表达均明显增强。重要的是，西地那非（PDE5的抑制剂）可以有效抑制PDE5活性的升高，并缓解SHR大鼠的ANP抵抗。相似的，有氧运动训练显著强化ANP的舒血管活性，增强SHR而不是WKY对照大鼠的血管舒张性。以上表明，有氧运动训练减轻钠尿肽抵抗，提示有氧运动或钠尿肽信号增敏剂可以有效防治高血压。本研究首次提出并验证了阻力血管钠尿肽抵抗促发高血压的科学假设。基于此科学假设，探讨了钠尿肽敏感性与高血压的关系，揭示了血管钠尿肽抵抗促发高血压的全新机制。为从改善钠尿肽敏感性的角度防治高血压提供了新的思路。