α2δ-1-Dependent NMDA Receptor Activity in the Hypothalamus Is an Effector of Genetic-Environment Interactions That Drive Persistent Hypertension

The interplay between genetic and environmental factors is critically involved in hypertension development. The paraventricular nucleus (PVN) of the hypothalamus regulates sympathetic output during stress responses and chronic hypertension. In this study, we determined mechanisms of synaptic plasticity in the PVN in chronic stress-induced persistent hypertension in male borderline hypertensive rats (BHR), the first offspring of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. In Wistar-Kyoto rats, chronic unpredictable mild stress (CUMS) increased arterial blood pressure (ABP) and heart rate, which quickly returned to baseline after GUMS ended. In contrast, in BHR, CUMS caused persistent elevation in ABP, which lasted at least 2 weeks after CUMS ended. CUMS also increased the mRNA level of alpha 2 delta-1 and synaptic protein levels of GluN1, alpha 2 delta-1, and alpha 2 delta-1-GluN1 complexes in the PVN in BHR. Furthermore, CUMS significantly increased the frequency of miniature EPSCs and the amplitude of NMDAR currents in spinally projecting PVN neurons in BHR; these increases were normalized by blocking NMDARs with AP5, inhibiting alpha 2 delta-1 with gabapentin, or disrupting the alpha 2 delta-1-NMDAR interaction with alpha 2 delta-1Tat peptide. Microinjection of AP5 or alpha 2 delta-1 Tat peptide into the PVN normalized elevated ABP and renal sympathetic nerve activity in stressed BHR. In addition, systemically administered gabapentin or memantine attenuated higher ABP induced by CUMS in BHR. Our findings indicate that chronic stress-induced persistent hypertension is mediated by augmented sympathetic outflow via alpha 2 delta-1-bound NMDARs in the PVN. This new information provides a cellular and molecular basis for how the genetic-environment interactions cause persistent hypertension.

Automated summary

The study reveals that chronic stress-induced persistent hypertension is mediated by enhanced sympathetic outflow via alpha 2 delta-1-bound NMDARs in the paraventricular nucleus. This provides a cellular and molecular basis for understanding how genetic and environmental factors interact to cause persistent hypertension.