BDNF downregulates β-adrenergic receptor-mediated hypotensive mechanisms in the paraventricular nucleus of the hypothalamus

Abstract

Brain derived neurotrophic factor (BDNF) is an important modulator of neuronal function, capable of mediating long‐term changes in neuronal structure and signaling in the central nervous system (CNS). Increased expression of BDNF in the PVN has been associated with elevated blood pressure (BP) and sympathetic nervous system activity. However, the mechanism mediating this effect of BDNF is unclear. BDNF is a modulator of catecholaminergic (CA‐ergic) neuronal function in the CNS, and could potentially influence CA‐ergic input to the PVN. The majority of CA‐ergic projections to the PVN come from the nucleus of the solitary tract (NTS), and these projections have been shown to exert a hypotensive effect. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates BP in part by diminishing the inhibitory input from NTS CA‐ergic neurons projecting to the PVN by downregulating β‐receptors in the PVN. Sprague‐Dawley (SD) rats received bilateral PVN injections of AAV2 viral vectors expressing either green fluorescent protein (GFP) or BDNF and bilateral NTS injections of phosphate‐buffered saline (PBS) or anti‐dopamine‐β‐hydroxylase‐conjugated saporin (DSAP), a neurotoxin selective to noradrenaline‐ and adrenaline‐synthesizing neurons. BDNF overexpression in the PVN without lesioning NTS CAergic neurons significantly increased mean arterial pressure (MAP) (BDNF+PBS: 115±3 mmHg, p<0.01 vs GFP+PBS: 96±2 mmHg). DSAP treatment increased MAP in the GFP group by ~13 mmHg, whereas DSAP treatment in the BDNF group did not significantly alter MAP. This suggests that BDNF overexpression in the PVN may interfere with CA‐ergic communication between the NTS and PVN. Since previous reports suggested that adrenergic β‐receptors exert an inhibitory effect on PVN neurons and lower BP, we tested whether BDNF overexpression in the PVN diminishes hypotensive effects of β‐receptor activation in the PVN. SD rats received bilateral PVN injections of AAV2 viral vectors expressing either GFP or BDNF. Three weeks later, BP responses to an injection of Isoprenaline (125 μM or 250 μM), a non‐selective β‐adrenergic agonist, into the PVN were recorded under alpha chloralosed‐urethane anesthesia. Our results showed that BDNF treatment significantly attenuated MAP responses to Isoprenaline compared to the GFP group in a dose dependent manner. In the GFP group, peak decrease in MAP in response to 125 μM and 250 μM Iso was −21±4 mmHg and −29±4 mmHg, compared with −4±1 mmHg (p<0.01) and −8±1 mmHg (p<0.001) in the BDNF group. To test if the reduced effect of Isoprenaline is due to a BDNF‐induced change in adrenergic receptor expression in the PVN, we assessed adrenergic receptor expression using quantitative RT‐PCR in PVN brain punches from SD rats previously injected with an AAV2 viral vectors expressing either GFP or BDNF. BDNF treatment significantly reduced the expression of β1 adrenergic receptor mRNA expression, whereas α1a, α1b, α2a, and β2 adrenergic receptors were unaffected by BDNF treatment. In summary, our findings indicate ...

Hypertension in Prenatally Undernourished Young-Adult Rats Is Maintained by Tonic Reciprocal Paraventricular–Coerulear Excitatory Interactions

“…Of note, higher α 1A -adrenoceptor mRNA [85] and unchanged α 1A , α 1B or α 1Dadrenoceptor mRNA [86,87] levels in the PVN of animals submitted to different experimental models of chronic hypertension have been reported. Chronic stress sensitizes the HPA axis to further acute stress (as measured by transient plasma ACTH increase) in rats, altogether with enhancing the response to α 1 -adrenergic receptor activation in the PVN [64].…”

The Role of the Paraventricular-Coerulear Network on the Programming of Hypertension by Prenatal Undernutrition

“…For example, α 1D up-regulates while the α 1A and α 1B subtypes down-regulate in a concentration-dependent manner during an agonist challenge (i.e., endogenous noradrenaline), and down-regulation of the latter was accompanied by reductions of mRNA (for review see [ 154 ]). Interestingly, higher levels of α 1A -adrenoceptor mRNA have reported in the PVN of rats suffering from chronic hypertension [ 155 ], but unchanged α 1A , α 1B , or α 1D -adrenoceptor mRNA in the whole hypothalamus [ 156 ] and the VPN [ 157 ] has also been reported. Besides, chronic stress (which is often accompanied by hypertension) sensitizes the HPA axis to further acute stress (as measured by transient plasma ACTH increase) in rats, enhancing the response to α 1 -adrenergic receptor activation in the PVN [ 158 ].…”

Hypothalamic miR-204 Induces Alteration of Heart Electrophysiology and Neurogenic Hypertension by Regulating the Sympathetic Nerve Activity: Potential Role of Microbiota

“…The paraventricular nucleus (PVN) of the hypothalamus plays an important role in regulating SNA [19]. Recent studies showed that increased levels of the brain-derived neurotrophic factor (BDNF) in the PVN led to increased sympathetic activity, BP, and arrhythmia [20][21][22][23]. Interestingly, miR-204 is highly expressed in the hypothalamus.…”