Transcriptomic Remodeling of the Hypothalamic Paraventricular Nucleus in Pregnant Spontaneously Hypertensive Rats: Autonomic Dysfunction and Neuroimmune Signature

Chronic hypertension significantly alters the transcriptomic response of the hypothalamic paraventricular nucleus during pregnancy, with 951 genes affected in spontaneously hypertensive rats.

Summary and findings

The study investigated the transcriptomic and cardiovascular autonomic profiles in pregnant normotensive Wistar rats and spontaneously hypertensive rats (SHRs). Pregnant SHRs exhibited significant transcriptomic reprogramming with 951 differentially expressed genes (DEGs) compared to 33 DEGs in Wistars. Notably, 95.9% of hypertension-altered genes showed active directional reversal during pregnancy in SHRs.

Abstract

<title>Abstract</title> <p> <bold>Introduction:</bold> Gestational adaptations require central autonomic recalibration via the hypothalamic paraventricular nucleus (PVN), yet how chronic hypertension alters its transcriptomic response during pregnancy remains unknown. We investigated PVN transcriptomic and cardiovascular autonomic profiles in pregnant normotensive (Wistar) and spontaneously hypertensive rats (SHRs) to uncover mechanisms underlying gestational hypothalamic adaptations to hypertension. <bold>Methods</bold> : Radiotelemetry-equipped Wistar rats and SHRs were evaluated for blood pressure, short-term variability, and baroreflex sensitivity alongside PVN bulk RNA-sequencing across virgin and late-pregnant states. <bold>Results</bold> : Both strains exhibited physiological gestational blood pressure drops. However, pregnant SHRs displayed blunted chronotropic reactivity, elevated cardiac sympathetic drive (increased LF HR and LF/HF ratio), and a doubling of spontaneous baroreflex sensitivity. Transcriptomically, pregnant Wistars showed a minimal homeostatic response (33 DEGs: e.g. <italic>Cish, Igfbp3, Irf7</italic> ). In stark contrast, pregnant SHRs underwent massive transcriptomic reprogramming (951 DEGs), marked by loss of astrocytic potassium buffering ( <italic>Kcnj10</italic> , <italic>Kcnb1</italic> ), chaperone depletion ( <italic>Hspa1a</italic> , <italic>Hspa1b</italic> ), excitatory neuropeptide elevation ( <italic>Hcrt</italic> , <italic>Trh</italic> ), and neuroimmune activation ( <italic>Zap70</italic> , <italic>Fcrl2, Itgam, Cmklr1</italic> ). Crucially, intersecting baseline hypertensive DEGs with gestational shifts in SHRs unmasked a significant inverse correlation, where 95.9% of hypertension-altered genes (140/146) underwent active directional reversal during pregnancy ( <italic>Hspa1a, Hspa1b, Ptgds, Per1</italic> ), enriching for translational, ribosomal, and bioenergetic pathways. <bold>Conclusion:</bold> Pre-existing chronic hypertension converts gestational PVN adaptation from a subtle homeostatic adjustment into an extensive genomic requirement (951 vs 33 DEGs). This massive transcriptomic remodeling represents an active counter-regulatory program in SHRs to sustain pregnancy to term, mitigating autonomic risk via heightened baroreflex sensitivity </p>

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