# Precision Editing of Myosin Phosphatase as a Novel Approach for Vasodilator Sensitization and Lowering of Blood Pressure in Hypertension

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2020 · —

## Abstract

High blood pressure (BP) is endemic, and despite vasodilator and diuretic therapy, still accounts for much
cardiovascular morbidity (heart failure, stroke) and mortality in the veteran population. Our studies focus on
Myosin Phosphatase (MP), which by de-phosphorylating myosin causes smooth muscle relaxation. MP is the
target of most constrictor and dilator signaling pathways that regulate vascular tone and thereby control BP. Over
years of study we have proposed a model in which alternative splicing of Exon 24 (E24) of the MP regulatory
subunit Mypt1 tunes vascular smooth muscle sensitivity to nitric oxide (NO)/ cGMP-mediated vasorelaxation.
Inclusion of the 31 nt E24 shifts the reading frame, thereby coding for an isoform of Mypt1 lacking the C-
terminal leucine zipper (LZ) motif required for cGMP-dependent kinase (cGK1α) activation of MP and
vasorelaxation. Others have shown that the inhibitory subunit of MP, CPI17, is a key target of signals that inhibit
MP and thereby cause vasoconstriction. The increased vascular resistance of hypertension is in part due to
reduced bio-availability of NO reducing vasodilator signaling, and neurohumoral activation increasing
vasoconstrictor signaling.
 Here we propose to test in an animal model of hypertension novel strategies involving precision editing of
the MP regulatory and inhibitory subunits aimed at shifting the balance of constrictor and dilator signaling in
order to lower vascular resistance and BP. Aims 1 and 2 will test vasodilator sensitization via precision editing
of MP regulatory subunit Mypt1 Exon 24 (E24). Aim 3 will test vasoconstrictor de-sensitization via precision
editing of the MP inhibitory subunit CPI17.
Aim 1 will develop Adeno-Associated Viral delivery of Crispr/Cas9 editing (deletion) of E24 to test if this
approach can reverse vasodysfunction in the AngII mouse model of hypertension.
Aim 2 will use our recently developed and validated Cre-Lox mouse model that achieves robust editing of the
same target, and compares approaches of primordial prevention vs treatment after hypertension is established.
Aim 3 will develop Adeno-Associated Viral delivery of Crispr/Cas9 editing of CPI17 to test if this approach can
suppress the increased vasoconstrictor signaling in the AngII mouse model of hypertension.
 Molecular assays will determine mechanisms by which dilator and constrictor signals are integrated by
MP in the control of BP in normal and hypertensive animals, and how this balance is altered by precision editing
of the MP subunits. These experiments, with high potential for translation to Veterans, will test a novel
strategy of vasodilator sensitization/vasoconstrictor desensitization for permanent lowering of BP, and
will define mechanisms by which signals converge on MP to cause vasodysfunction in models of
hypertension.

## Key facts

- **NIH application ID:** 9842267
- **Project number:** 5I01BX004443-02
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Steven A. Fisher
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842267

## Citation

> US National Institutes of Health, RePORTER application 9842267, Precision Editing of Myosin Phosphatase as a Novel Approach for Vasodilator Sensitization and Lowering of Blood Pressure in Hypertension (5I01BX004443-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842267. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*