Department of Pharmacology, University of Vermont, Burlington, Vermont.
Am J Physiol Heart Circ Physiol. 2019 Dec 1;317(6):H1258-H1271. doi: 10.1152/ajpheart.00478.2019. Epub 2019 Oct 11.
Brain-derived neurotrophic factor (BDNF) is upregulated in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli such as stress and hyperosmolality, and BDNF acting in the PVN plays a key role in elevating sympathetic activity and blood pressure. However, downstream mechanisms mediating these effects remain unclear. We tested the hypothesis that BDNF increases blood pressure, in part by diminishing inhibitory hypotensive input from nucleus of the solitary tract (NTS) catecholaminergic neurons projecting to the PVN. Male Sprague-Dawley rats received bilateral PVN injections of viral vectors expressing either green fluorescent protein (GFP) or BDNF and bilateral NTS injections of vehicle or anti-dopamine-β-hydroxylase-conjugated saporin (DSAP), a neurotoxin that selectively lesions noradrenergic and adrenergic neurons. BDNF overexpression in the PVN without NTS lesioning significantly increased mean arterial pressure (MAP) in awake animals by 18.7 ± 1.8 mmHg. DSAP treatment also increased MAP in the GFP group, by 9.8 ± 3.2 mmHg, but failed to affect MAP in the BDNF group, indicating a BDNF-induced loss of NTS catecholaminergic hypotensive effects. In addition, in α-chloralose-urethane-anesthetized rats, hypotensive responses to PVN injections of the β-adrenergic agonist isoprenaline were significantly attenuated by BDNF overexpression, whereas PVN injections of phenylephrine had no effect on blood pressure. BDNF treatment was also found to significantly reduce β-adrenergic receptor mRNA expression in the PVN, whereas expression of other adrenergic receptors was unaffected. In summary, increased BDNF expression in the PVN elevates blood pressure, in part by downregulating β-receptor signaling and diminishing hypotensive catecholaminergic input from the NTS to the PVN. We have shown that BDNF, a key hypothalamic regulator of blood pressure, disrupts catecholaminergic signaling between the NTS and the PVN by reducing the responsiveness of PVN neurons to inhibitory hypotensive β-adrenergic input from the NTS. This may be occurring partly via BDNF-mediated downregulation of β-adrenergic receptor expression in the PVN and results in an increase in blood pressure.
脑源性神经营养因子（BDNF）在响应高血压刺激（如应激和高渗）时在上丘脑室旁核（PVN）中上调，并且在 PVN 中起作用的 BDNF 发挥关键作用，可升高交感神经活性和血压。然而，介导这些效应的下游机制仍不清楚。我们检验了如下假设，即 BDNF 通过减少来自投射到 PVN 的孤束核（NTS）儿茶酚胺能神经元的抑制性降压输入，部分增加血压。雄性 Sprague-Dawley 大鼠接受双侧 PVN 注射表达绿色荧光蛋白（GFP）或 BDNF 的病毒载体和双侧 NTS 注射载体或抗多巴胺-β-羟化酶结合的相思豆毒素（DSAP），后者是一种选择性破坏去甲肾上腺素能和肾上腺素能神经元的神经毒素。PVN 中 BDNF 的过表达而不进行 NTS 损伤可使清醒动物的平均动脉压（MAP）升高 18.7±1.8mmHg。在 GFP 组中，DSAP 处理也增加了 MAP，升高了 9.8±3.2mmHg，但未能影响 BDNF 组的 MAP，表明 BDNF 引起的 NTS 儿茶酚胺能降压作用丧失。此外，在氯醛糖-乌拉坦-麻醉的大鼠中，PVN 注射β-肾上腺素能激动剂异丙肾上腺素引起的降压反应明显被 BDNF 的过表达减弱，而 PVN 注射苯肾上腺素对血压无影响。还发现 BDNF 处理也显著降低了 PVN 中的β-肾上腺素能受体 mRNA 表达，而其他肾上腺素能受体的表达不受影响。总之，PVN 中 BDNF 表达的增加升高了血压，部分原因是通过下调β-受体信号和减少来自 NTS 的降压儿茶酚胺能输入来降低 PVN 神经元对来自 NTS 的抑制性降压β-肾上腺素能输入的反应性。我们已经表明，作为血压的关键下丘脑调节剂的 BDNF 通过降低 PVN 神经元对来自 NTS 的抑制性降压β-肾上腺素能输入的反应性，破坏了 NTS 和 PVN 之间的儿茶酚胺能信号传递。这可能部分是通过 BDNF 介导的 PVN 中β-肾上腺素能受体表达的下调而发生的，从而导致血压升高。
