In mice, inhibition of p75NTR with Marimastat or LM11A-31 significantly increased cardiac sympathetic nerve density compared to high-dose Angiotensin II alone.
Does inhibition of p75NTR cleavage or signaling prevent sympathetic nerve degeneration in mice with AngII-induced hypertension?
Inhibition of p75NTR prevents sympathetic nerve degeneration in the heart during AngII-induced hypertension in mice, suggesting a role for oxidative stress and p75NTR in cardiac sympathetic denervation.
Hypertension is a common cardiovascular disease that increases the risk of stroke and heart failure. We previously used an Angiotensin II (AngII) infusion (700 ng/kg*min) to generate hypertension in mice and found that 4 weeks of hypertension led to substantial loss of sympathetic nerves in the heart. Additional studies showed that just 7 days of AngII infusion led to both oxidative stress and nerve degeneration in the heart. This study aimed to identify the mechanism of sympathetic nerve degeneration in the heart during AngII hypertension. Oxidative stress can stimulate sympathetic axon degradation via cleavage of the p75 neurotrophin receptor (p75NTR). We hypothesized that AngII-induced oxidative stress triggers sympathetic nerve loss in the heart via p75NTR. We tested the role of oxidative stress using a dose of AngII (400 ng/kg*min) that does not trigger oxidative stress in the heart. We tested the role of p75NTR by treating mice with 700 ng/kg*min AngII with or without the protease inhibitor Marimastat which blocks p75NTR cleavage, or the p75NTR specific inhibitor LM11A-31. Mice were implanted with minipumps releasing AngII and then 3 days later treated with saline vehicle, Marimastat (20 mg/kg), or LM11A-31(25 mg/kg). Mean arterial pressure (MAP) was quantified in all mice. Mice were sacrificed after 7 days, and sympathetic nerves were identified by immunohistochemistry for tyrosine hydroxylase (TH). Nerves were quantified using ImageJ by two researchers independently. Three regions of each heart were analyzed: the left ventricle (LV), right ventricle (RV), and intraventricular septum (IVS). Fiber density was averaged across 3 sections per heart. Staining was carried out in batches and nerve density was normalized within each batch. AngII infusion at 400 ng/kg*min (155±22 mmHg) and 700 ng/kg*min (142±14 mmHg, raised MAP significantly compared to saline (93±17mmHg) (Mean±SD, n=5-9). However, the lower dose of AngII did not stimulate oxidative stress in the heart or alter sympathetic nerve density compared to saline controls. Ang vs Saline: LV 0.98±0.15% vs. 1.00±0.14%, IVS 0.78±0.31% vs. 1.00±0.24%, RV 1.25±0.22% vs. 1.00±0.21% (Mean±SD, n=5-9). Treatment with Marimastat (20 mg/kg) significantly increased sympathetic nerve density compared to high dose AngII alone. AngII + Mar vs AngII: LV 2.40±0.55% vs. 1.00±0.40%, IVS 3.25±1.46% vs. 1.00±0.61%, RV 1.52±0.50% vs. 1.00±0.54% (Mean±SD, n=4-5). Likewise, AngII+LM11A-31 treatment increased nerve density compared to AngII alone. Saline vs AngII vs AngII+LM11A-31: LV 1.00±0.18%; 0.16±0.13%; 0.82±0.22, the IVS 1.00±0.26%; 0.09±0.05%; 0.63±0.22 and the RV 1.00±0.13%; 0.35±0.09%; 1.27±0.28 (Mean±SD, n=3-6). Together these data strongly support the hypothesis that AngII stimulates oxidative stress in the heart, which causes sympathetic axon degeneration via the p75NTR. Funding for this project was provided by NIH #HL09305 and the MJ Murdock Charitable Trust 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.
Nichols et al. (Fri,) conducted a other in Hypertension. Marimastat or LM11A-31 vs. Angiotensin II alone or saline was evaluated on Sympathetic nerve density in the heart. In mice, inhibition of p75NTR with Marimastat or LM11A-31 significantly increased cardiac sympathetic nerve density compared to high-dose Angiotensin II alone.