Perineuronal nets (PNNs), specialized extracellular matrix (ECM) structures surrounding selective neuronal populations, are key regulators of synaptic stability and plasticity. Within the hypothalamic arcuate nucleus (ARC), PNNs enmesh both agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neurons, which are central to metabolic and autonomic regulation. In the current study, we investigated whether these PNNs are remodeled by hypertension by measuring temporal and cell-type-specific changes in ARC PNNs during the development of deoxycorticosterone acetate (DOCA)-salt hypertension. To induce hypertension, mice received DOCA-salt (50 mg DOCA+0.9% saline in drinking water) while controls received Sham treatment (sham pellet + regular drinking water) for 3, 7, 14, or 21 days (n = 3-6 mice/group). PNNs were visualized using Wisteria floribunda agglutinin (WFA) labeling and quantified in MATLAB. While PNN area (WFA-labeled area per ARC) was unchanged by DOCA-salt at Day 3 (2116 ± 1458 vs. 2419 ± 1297 µm2; p = 0.0127), it was significantly increased on both Day 7 (2889 ± 1515 vs. 2377 ± 1210 µm2; p = 0.0158) and Day 14 (3072 ± 2572 vs. 1784 ± 2074 µm2; p = 0.0006). Although the PNN area remained increased on Day 21, the effect was reduced and no longer achieved statistical significance (2368 ± 1678 vs. 2144 ± 1109; p = 0.273). In contrast, ARC PNN mean fluorescence intensity (MFI, fold change) was not robustly impacted by DOCA-salt treatment: the modest MFI reduction detected on Day 7 (0.9 ± 0.02 vs. 1.0 ± 0.02; p = 0.0051) was transient, having resolved by Days 14 (1.1 ± 0.02 vs. 1.00 ± 0.01; p = 0.0024) and 21 (1.1 ± 0.03 vs. 1.0 ± 0.02; p = 0.0068). These results reveal complex, transient effects of DOCA-salt treatment on ARC PNNs. We next quantified the effects of DOCA-salt on PNN enmeshment of AgRP and POMC neurons. Under normotensive conditions, PNNs primarily enmesh AgRP neurons (24 ± 3 cells/ARC, 20ARC/4 mice), with minimal enmeshment of POMC neurons (3 ± 1 cells/ARC, 8ARC/3 mice). After 2 wk of DOCA-salt treatment, both the number (45 ± 2 vs. 24 ± 3 cells/ARC; p < 0.0001) and proportion (91.8 % ± 2.0 vs. 56.8 % ± 6.3; p < 0.0001) of AgRP neurons surrounded by PNNs was robustly increased compared with Sham-treated controls. In contrast, neither the number (3 ± 1 cells/ARC, p = 0.899) nor the proportion (18.91 % ± 4.37 vs. 20.15 % ± 4.19; p = 0.840) of POMC neurons enmeshed by PNNs was impacted by DOCA-salt treatment. Together, these data demonstrate dynamic remodeling of ARC PNNs during DOCA-salt-induced hypertension, characterized by a robust, selective structural reinforcement around AgRP neurons. This type of targeted structural plasticity suggests that in hypertension, AgRP neuron function is impacted by PNN reorganization. In light of recent evidence linking these neurons to blood pressure control, additional investigation into links between AgRP neuron activity, PNN enmeshment, and blood pressure dysregulation is warranted. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Verma et al. (Fri,) studied this question.