Effects And Mechanisms Of Activin A In PVN On Regulation Of Arterial Pressure In Rats

Activin A is a multifunctional cytokine belonging to the transforming growth factor beta(TGF-β) superfamily. It plays an important role in a variety of tissues and organs differentiation and development, cell proliferation and apoptosis. Follistatin(FS) is an activin-binding protein which can bind with activin specifically to neutralize biological effect of activin.The hypothalamic paraventricular nucleus(PVN)not only can regulate autonomic nervous function, but also is one of the important center of neuroendocrine, as well as an important center in regulating arterial pressure.However, whether activin A in the PVN is involved in regulation of arterial pressure is still unknown. Therefore, this study is focused on the effects and mechanisms of activin A in the PVN on regulation of arterial pressure in rats by RT-PCR,immunohistochemical staining, cerebral stereotaxis, ELISA methods and so on.The results of RT-PCR showed that activin A, activin type IIA receptor(Act RIIA), activin type IIB receptor(Act RIIB), FS and Smad2, 3, 4 m RNA can be detected in PVN of both Wistar-Kyoto(WKY) and spontaneous hypertensive rats(SHR). Moreover, all of the expressions in the PVN of SHR rats were much higher than those of WKY rats. Immunohistochemical staining results showed that activin A,Act RIIA and FS proteins were also significantly stronger in PVN of SHR rats than those of WKY rats, which was consistent with the results of RT-PCR. These results suggest that activin A might be involved in the regulation of the PVN neurons function in an autocrine/paracrine manner, and there is quantity difference of expressions of activin A and its signal transduction molecules in the PVN between SHR and WKY rats. Microinjection of activin A into PVN can increase arterial pressure in both WKY and SHR rats significantly, and the extent of increase of arterial pressure was higher in SHR rats than that in WKY rats. Meanwhile, the effect of FS in the PVN on arterial pressure was also measured. Interestingly, microinjectionof FS into the PVN can decrease the arterial pressure in SHR rats, but there is no effect in WKY rats. Activin A induced the primary cultured PVN neuron of WKY rats to release angiotensin II(Ang II) and arginine vasopressin(AVP) into the culture supernatant. At the same time, activin A can promote the expressions of angiotensin converting enzyme(ACE), angiotensin II type 1 receptor(AT1), AVP and arginine vasopressin recptor(AVPR) m RNA, as well as the expressions of Act RIIA, Smad3 and FS m RNA, but activin A cannot affect the expressions of Act RIIB, Smad2, 4m RNA.All the data in this study revealed that activin A and activin A receptors, Smads and FS expressions in the PVN of SHR rats were higher than those of WKY rats, and activin A in PVN of SHR rats elevated much higher arterial pressure than that of WKY rats. Therefore, activin A may regulate the PVN neurons function in an autocrine/paracrine manner to regulate arterial pressure, which is mediated by Act RIIA-Smad3 signal transduction pathway. Moreover, activin A promoting the synthesis and release of Ang II and AVP, expressions of AT1 and AVPR were also involved in the formation of hypertension of SHR rats. This study not only revealed that function of activin A in PVN on arterial pressure, but also elucidated the mechanism of hypertension, which provided a basic research for searching for new therapeutic target of hypertension in the center nerve system.