Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation

Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.

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“…After the primary and secondary antibodies were stained, nuclei were stained with DAPI at room temperature for 20 min. 43 …”

Section: Methodsmentioning

confidence: 99%

Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4

et al. 2021

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“…SD rats were randomly divided into two groups. The hypertension group was induced by N'‐Nitro‐L‐Arginine‐methyl ester (L‐NAME), 9 which was injected intraperitoneally (40 mg/kg/d) for 4 weeks. 34 , 35 , 36 The systolic blood pressure (SBP) of all rats was measured weekly.…”

Section: Methodsmentioning

confidence: 99%

“…BRx afferent loop initiates the sensing BP fluctuation by baroreceptor terminals distributed in the aorta 1 operated by mechanosensitive PIEZOs channels 2 , 3 , 4 to the cell body of the 1 st ‐order neurons 5 , 6 in the nodose ganglia (NG), and then to the cell body of the 2 nd ‐order neurons 7 , 8 in the nucleus tractus solitarius (NTS) by forming the synapses through its central projection and the efferent loop innervates to the heart and blood vessel. Extensive animal studies have demonstrated that BRx afferent function is critical to stabilize the BP under physiological and hypertensive conditions, 7 , 9 , 10 , 11 , 12 , 13 , 14 suggesting that dysfunction of BRx afferent function is crucial for the development of both primary and secondary hypertension.…”

Section: Introductionmentioning

confidence: 99%

Bradykinin‐mediated estrogen‐dependent depressor response by direct activation of female‐specific distribution of myelinated Ah‐type baroreceptor neurons in rats

Feng

Fan

et al. 2021

CNS Neurosci Ther

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Aim To understand the direct impact of bradykinin in autonomic control of circulation through baroreflex afferent pathway. Methods The mean arterial pressure (MAP) was monitored while bradykinin and its agonists were applied via nodose (NG) microinjection, the expression of bradykinin receptors (BRs) in the NG (1st‐order) and nucleus tractus solitarius (NTS, 2nd‐order) were tested in adult male, age‐matched female, and ovariectomized rats under physiological and hypertensive conditions. Additionally, bradykinin‐induced depolarization was also tested in identified baroreceptor and baroreceptive neurons using whole‐cell patch‐clamp technique. Results Under physiological condition, bradykinin‐induced dose‐ and estrogen‐dependent reductions of MAP with lower estimated EC50 in females. B2R agonist mediated more dramatic MAP reduction with long‐lasting effect compared with B1R activation. These functional observations were consistent with the molecular and immunostaining evidences. However, under hypertensive condition, the MAP reduction was significantly less dramatic in N’‐Nitro‐L‐Arginine‐methyl ester (L‐NAME) induced secondary and spontaneous hypertension rats in males compared with female rats. Electrophysiological data showed that bradykinin‐elicited concentration‐dependent membrane depolarization with discharges during initial phase in identified myelinated Ah‐types baroreceptor neurons, not myelinated A‐types; while, higher concentration of bradykinin was required for depolarization of unmyelinated C‐types without initial discharges. Conclusion These datasets have demonstrated for the first time that bradykinin mediates direct activation of baroreflex afferent function to trigger estrogen‐dependent depressor response, which is due mainly to the direct activation/neuroexcitation of female‐specific myelinated Ah‐type baroreceptor neurons leading to a sexual dimorphism in parasympathetic domination of blood pressure regulation via activation of B2R/B1R expression in baroreflex afferent pathway.

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A Second Wave for the Neurokinin Tac2 Pathway in Brain Research

Abed¹,

Reynolds²,

Dehorter

2021

Biological Psychiatry

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Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation

Abstract: The estrogen-dependent NKRs' expression in baroreflex afferent pathway participates at least partially in sexual-dimorphic and SP-mediated BP regulation under physiological and hypertensive conditions.

Cited by 8 publications

References 60 publications

Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4

Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4

Bradykinin‐mediated estrogen‐dependent depressor response by direct activation of female‐specific distribution of myelinated Ah‐type baroreceptor neurons in rats

A Second Wave for the Neurokinin Tac2 Pathway in Brain Research

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