MIF: A novel CNS regulator of cardiovascular function

描述（由申请人提供）：已知肽血管紧张素II （Ang II）是负责神经源性高血压的中枢机制的主要参与者。Ang II在脑内起升高血压的作用，其生理机制包括血管紧张素1型受体（AT1-R）介导的下丘脑室旁核交感血管运动神经元的激活。PVN是整合心血管状态信息的关键中继点，并通过投射到延髓吻侧腹外侧（RVLM）等区域的传入神经活动增加，引起交感神经流出和血压增加。有很多证据表明，Ang II的中枢作用在神经源性高血压中被放大并导致其发生。因此，了解正常动物中Ang II如何通过大脑调节心血管功能，包括作用和调节机制，对于揭示高血压中枢性Ang II/AT1R机制持续过度活动的原因以及最终开发新的治疗干预措施至关重要。我们之前已经证实，在正常大鼠中，MIF是一种由Ang ii诱导的AT1R介导的PVN向RVLM交感神经元的兴奋和Ang ii诱导的升压作用的细胞内负调节因子。我们还确定，在表现慢性中枢AT1R激活的神经源性高血压动物模型中，包括自发性高血压大鼠（SHR），这种MIF调节机制是功能失调的。当前提案的广泛目标是研究血管紧张素2型受体（AT2R）与MIF在正常和高血压大鼠PVN通过AT1R调节Ang II的心血管作用中的作用。该策略基于我们的初步观察，即Ang II和MIF均可引起PVN神经元中AT2R表达的显著增加，并且正常大鼠PVN中AT2R水平的增加会减弱at1r介导的对中枢神经系统注射Ang II的压力反应。基于此，我们发表了关于Ang II和MIF在PVN控制血压中的作用，并记录了AT2R的神经元抑制作用，我们提出了以下总体假设：(a) MIF诱导PVN中功能性内源性AT2R向RVLM神经元的表达是该蛋白对Ang II/AT1R心血管作用长期负调控的关键因素；(b)这种MIF/AT2R调控机制在SHR的PVN中不存在，但可以通过MIF在该位点的神经元表达增加来恢复。这些假设将通过以下目的进行验证：(1)研究MIF对正常血压大鼠PVN至RVLM神经元中AT2R表达的影响；(2)确定PVN对RVLM神经元响应于MIF诱导的AT2R是否对相同细胞的at1r介导的兴奋产生拮抗作用；(3)探讨AT2R在PVN中MIF对正常大鼠和SHR中Ang II/ at1r诱导的心血管反应的抑制作用。这些目标将通过多学科（细胞、分子、生理）的方法进行研究。

DESCRIPTION (provided by applicant): The peptide angiotensin II (Ang II) is known to be a major participant in the central mechanisms that are responsible for neurogenic hypertension. Ang II acts within the brain to increase blood pressure, and the physiological mechanisms involved in this effect include angiotensin type 1 receptor (AT1-R)-mediated activation of sympathetic vasomotor neurons at the paraventricular nucleus of the hypothalamus (PVN). The PVN is a key relay point for integrating information on cardiovascular status and elicits increased sympathetic outflow and blood pressure, via increases in the activity of efferents projecting to areas such as the rostral ventrolateral medulla (RVLM). There is much evidence that this central action of Ang II is amplified in and contributes to neurogenic hypertension. Thus, understanding how Ang II regulates cardiovascular function via the brain in normal animals, including mechanisms of action and regulation, is critical and highly significant to uncovering the reasons for persistent over activity of central Ang II/AT1R mechanisms in high blood pressure and ultimately to the development of new therapeutic interventions. We established previously that in normal rats MIF is an Ang II-inducible intracellular negative regulator of the AT1R mediated excitation of PVN to RVLM sympathetic neurons and Ang II-induced pressor effect. We also determined that this MIF regulatory mechanism is dysfunctional in animal models of neurogenic hypertension that exhibit chronic central AT1R activation, including spontaneously hypertensive rats (SHR). The broad goal of the current proposal is to investigate the role of angiotensin type 2 receptors (AT2R), in concert with MIF, in regulating the cardiovascular actions of Ang II via AT1R at the PVN in normal and hypertensive rats. This strategy is based on our preliminary observations that both Ang II and MIF elicit profound increases in the expression of AT2R in PVN neurons, and that increased levels of AT2R in normotensive rat PVN blunts the AT1R-mediated pressor response to CNS-injected Ang II. Based on this, our published work on Ang II and MIF in the PVN control of blood pressure, and documented neuronal inhibitory actions of AT2R we developed the following overall hypotheses: (a) MIF induced expression of functional endogenous AT2R in PVN to RVLM neurons is a critical element of the longer term negative regulation by this protein over Ang II/AT1R cardiovascular actions; (b) This MIF/AT2R regulatory mechanism is absent from the PVN of SHR, but can be restored by the increased neuronal expression of MIF at this site. These hypotheses will be tested via the following aims: (1) Investigate the effects of MIF on AT2R expression in PVN to RVLM neurons of normotensive rats and SHR; (2) Determine whether AT2R, induced in PVN to RVLM neurons in response to MIF, produce effects that are antagonistic to AT1R-mediated excitation of the same cells; (3) Investigate the role of AT2R in the PVN in the inhibitory effects of MIF over Ang II/AT1R-induced cardiovascular responses in normotensive rats and SHR. These aims will be studied through a multidisciplinary (cellular, molecular, physiological) approach. PUBLIC HEALTH RELEVANCE: In the broadest sense our research is aimed at understanding how the central nervous system (CNS) controls blood pressure in healthy individuals, and how faults in these control mechanisms contribute to hypertension. We have identified macrophage migration inhibitory factor in the brain as a regulator that helps to keep blood pressure in check and stop it from exceeding normal limits. The immediate goal of the proposed studies is to determine how macrophage migration inhibitory factor works in concert with angiotensin type 2 receptors in the CNS to help regulate blood pressure under normal conditions, and whether this regulation fails in hypertension. Information gained from these studies may lead to the development of novel therapeutic targets for hypertension.