# Precision Editing of Myosin Phosphatase for Vasodilator Sensitization in Hypertension

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $347,625

## Abstract

Project Summary
High blood pressure is endemic, and despite vasodilator and diuretic therapy still accounts for much world-wide
cardiovascular morbidity (heart failure, stroke) and mortality. Our studies focus on Myosin Phosphatase (MP)
which by de-phosphorylating myosin causes smooth muscle relaxation. MP is the target of constrictor and dilator
signaling pathways that regulate vascular tone and thereby control BP. 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 NO/cGMP-mediated vasorelaxation. Inclusion of the 31 nt E24 shifts the reading frame, thus coding for a C-
terminal sequence lacking the leucine zipper (LZ) motif required for cGMP-dependent kinase (cGK1α) activation
of MP and vasorelaxation. This vasodilator pathway may also be activated by ROS mediated oxidation of cGK1α
and its downstream targets including MP. The increased vascular resistance of hypertension may in part be due
to reduced bio-availability of NO and increased ROS generation reducing vasodilator signaling and increasing
vascular resistance. Here we propose to test the hypothesis that precision editing of Mypt1 E24 will reduce
vascular resistance to blood flow and permanently lower blood pressure (BP) in hypertension. Aim 1
uses complementary approaches of A) Cre-Lox B) Adeno-Associated Viral delivery of Crispr/Cas9, for precision
editing of E24 to test if this approach can reverse vasodysfunction in the AngII model of hypertension. It
compares approaches of primordial prevention vs treatment after hypertension is established. Molecular assays
will determine how NO/cGMP/ROS activate MP, testing a novel 2-pool “brake and accelerator” model for the
integration of dilator and constrictor signals in the control of MP, and thus blood pressure, in hypertension.
 The hypertensive diathesis may initiate early in life as evidenced by tracking of BP throughout the life
course. Lifetime BP is most strongly related to cardiovascular outcomes, and effective lowering of BP in maturity
does not normalize cardiovascular morbidity and mortality. These provide compelling rationale for the study of
programming of hypertension and its primordial prevention early in life. We have shown that the switch to the
E24+ (“cGMP resistant”) isoform of Mypt1 occurs during adolescence as part of arterial maturation and
concordant with increasing vasoconstrictor function and BP. This process is accelerated by early life stress, an
important risk factor in the development of hypertension. Aim 2 will test the ability of precision editing of E24
early in life to mitigate the deleterious effect of stress early, or throughout, the life course, on arterial function and
programming. It will also test if primordial prevention of vasodysfunction via precision editing of E24 in early life
is more effective as compared to after hypertension is well established. We expect that this novel strategy of
precision edit...

## Key facts

- **NIH application ID:** 9894837
- **Project number:** 5R01HL142971-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Steven A. Fisher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,625
- **Award type:** 5
- **Project period:** 2019-03-20 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894837

## Citation

> US National Institutes of Health, RePORTER application 9894837, Precision Editing of Myosin Phosphatase for Vasodilator Sensitization in Hypertension (5R01HL142971-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9894837. Licensed CC0.

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