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Brain‐derived neurotrophic factor (BDNF) acting within the paraventricular nucleus induces blood pressure elevations under permissive control of angiotensin II and mediates pressor responses to acute stress

Brain‐derived neurotrophic factor (BDNF) exerts diverse effects on neuronal function throughout the central nervous system by regulating gene expression, synaptic function and ion channels via its high‐affinity tyrosine kinase receptor TrkB. The paraventricular nucleus of the hypothalamus (PVN) plays a key role in mediating stress‐induced neuroendocrine responses, and here we tested the novel hypothesis that within the PVN, BDNF is a regulator of cardiovascular function during stress that elicits sympathoexcitation and blood pressure elevations in an angiotensin II (Ang II)‐dependent manner. This hypothesis is based on findings that BDNF expression increases rapidly in the PVN during stress and our previous studies demonstrating that overexpression of BDNF in the PVN leads to significant blood pressure elevations that are mediated, at least in part, by Ang II signaling in the PVN. First, to test acute actions of BDNF in the PVN, Sprague Dawley (SD) rats were equipped with femoral artery and vein catheters for the measurement of blood pressure and infusion of drugs under isoflurane anesthesia. After surgical procedures, anesthesia was gradually switched to iv. α‐chloralose (12–20 mg/kg/h) and cardiovascular responses to intra‐PVN injections of BDNF (12.5 ng) were analyzed following intra‐PVN pretreatment with the Ang II‐type 1 receptor (AT1R) inhibitor losartan (10 ng) or vehicle via a double barrel glass micropipette or after ganglionic blockade with hexamethonium (30 mg/kg, iv). BDNF induced marked increases in mean arterial pressure (MAP; peak increase: 31±4 mmHg; n=5) that were significantly attenuated by losartan (peak increase: 7±1 mmHg; n=5, p<0.01) and hexamethonium (peak increase: 10±1 mmHg; n=5, p<0.01) pretreatments. Additional in vitro experiments conducted on freshly isolated PVN brain punches indicated that BDNF (25 μg/mL, 37°C, 30 min incubation) significantly increased phosphorylation of TrkB receptors and that this effect was inhibited by losartan (10 μM) co‐treatment. To test if BDNF‐TrkB signaling in the PVN mediates cardiovascular responses to acute stress, SD rats were equipped with telemetry transmitters to measure blood pressure and received bilateral PVN injections of lentivirus vectors expressing either green fluorescent protein (GFP, for control; n=6) or TrkB.T1, a dominant negative truncated TrkB receptor variant lacking the intracellular tyrosine kinase module, that inhibits TrkB signaling (n=7). Rats were then subjected to acute water stress (15 min in 1‐cm deep, 25°C water) and acute restraint stress (60 min) 3 and 4 wks after vector injections. TrkB.T1 overexpression had no effect on baseline mean arterial pressure (MAP), but significantly reduced peak MAP elevations during water stress (GFP: 36±3 mmHg; TrkB.T1: 18±8 mmHg, p<0.01) and restraint stress (GFP: 42±4 mmHg; TrkB.T1: 30±2 mmHg, p<0.05). In conclusion, these findings indicate that BDNF acting within the PVN acutely increases blood pressure under permissive control of Ang II and AT1R and that this mechanism plays an important role in mediating pressor responses to acute stress.