{"doi":"10.1093/cvr/cvaf241","title":"Central command of hypertension: PVN-CRH neurons in the driver’s seat","abstract":"This editorial refers to ‘Unrevealing the role of hypothalamic corticotropin-releasing hormone neurons in blood pressure regulation in hypertension’, by H. Zhang et al., https://doi.org/10.1093/cvr/cvaf211. Hypertension remains a significant global health challenge.1 Mounting evidence points to central neural circuits as key contributors to hypertension pathology, but the specific circuitry involved in the control of blood pressure has remained elusive.2 The central nervous system substantially affects the progression and maintenance of hypertension, with the hypothalamus and particularly the paraventricular nucleus (PVN) identified as a critical regulator.3,4 The PVN merges inputs from central and peripheral sources to synchronize the hormonal responses and sympathetic output necessary for blood pressure regulation.5 Within the PVN, different neuronal populations exist comprised of pre-autonomic parvocellular neurons projecting to the spinal cord and rostral ventrolateral medulla (RVLM), regulating baroreflex function and sympathetic activity, along with magnocellular neurons that secrete vasopressin and oxytocin into the bloodstream.5,6 In hypertension models, the PVN displays increased oxidative stress and neuroinflammation, a decline in GABAergic (inhibitory) tone, and enhanced glutamatergic (excitatory) drive, thereby promoting sympathoexcitation and a chronic increase in blood pressure.7 Furthermore, neuropeptides such as vasopressin and corticotropin-releasing hormone (CRH) alongside angiotensin II in the PVN intensify these responses.5,8 These mechanisms highlight the significance of hypothalamic circuits in neurogenic hypertension and offer possible remedial targets. In this issue, using spontaneously hypertensive rats (SHR), Zhang et al.9 demonstrate the central role of PVN-CRH neurons in driving hypertension through peptidergic excitation of RVLM-projecting PVN neurons (Figure 1). First, they show that PVN-CRH neurons interface anatomically and functionally with PVN neurons projecting to the RVLM, a critical brainstem region for sympathetic regulation. By labeling PVN-CRH neurons with enhanced Green Fluorescent Protein and tracing PVN-RVLM neurons using a retrograde mCherry adeno-associated virus, the authors found that the two neuronal populations were anatomically distinct yet closely positioned. Furthermore, high-magnification images revealed that PVN-RVLM neurons are enwreathed by PVN-CRH neuron dendrites (Figure 1A). Optogenetic-mediated activation of PVN-CRH neurons increased the firing of PVN-RVLM neurons, an effect abolished by the CRH receptor antagonist astressin. Of note, astressin had no effect on baseline firing of either population, indicating that PVN-RVLM neurons are excited by CRH from PVN-CRH neurons. The specific CRHR isoform driving this behavior was determined in earlier work by the authors, where CRHR1, but not CRHR2, inhibition decreased the firing rate of PVN-RVLM neurons, reduced blood pressure, and renal sympathetic nerve activity (RSNA) in SHR.10 Graphical representation of Zhang et al.’s findings. A) Glutamatergic input drives activation of PVN-CRH neurons, which release CRH. PVN-CRH neuron dendrites enwreathe PVN-RVLM neurons, which are excited by released CRH. PVN-RVLM excitation results in increased sympathetic nerve activity (SNA) and blood pressure. B) SAP102, a GluN2B NMDAR transporter, is upregulated in SHR alongside decreased extrasynaptic and increased synaptic NMDAR activity, indicating increased SAP102 GluN2B trafficking and providing a potential explanation for increased PVN-CRH excitatory tone in SHR. C) SHR have increased basal PVN-CRH and PVN-RVLM activity compared to normotensive WKY rats. Glutamatergic input to PVN-CRH neurons elicits CRH release, which excites proximal PVN-RVLM neurons and drives increased SNA and blood pressure. Image created using Biorender. Interestingly, optical stimulation of PVN-CRH neurons did not alter spontaneous excitatory postsynaptic currents","journal":"Cardiovascular Research","year":2025,"id":581575,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1493522,"name":"Shikha Salhotra","orcid":null,"position":1,"is_corresponding":false},{"id":297602,"name":"Kamal Rahmouni","orcid":"0000-0001-5136-6748","position":2,"is_corresponding":false},{"id":1249621,"name":"Kai Vorhies","orcid":"0000-0002-8673-0703","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-19T02:58:51.328454Z","pmid":"41250854","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}