# E2F2 and Vascular Function

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $568,142

## Abstract

Project Summary
Despite intensive investigation, hypertension remains a major public health problem. The pathogenesis of
hypertension is incompletely characterized, and the potential role of transcriptional mechanisms is particularly
unclear. Previously, we have published evidence that the E2F2 transcription factor is crucial for maintaining
blood pressure (BP) homeostasis: mice carrying a deletion mutation of E2F2 are hypertensive, and their
arterial vessels are hypercontractile. Historically, E2F2 is considered a cell-cycle regulator; however, in
endothelial cells (ECs), E2F2 promotes the expression of endothelial converting enzyme 1b (ECE-1b), the
deactivating ECE-1 isoform, thus suppressing ECE-1 activity and endothelin-1 (ET-1) biogenesis. Our results
also suggest that Sam68, a Src-family–kinase (SFK) substrate, interacts with E2F2 and represses E2F2-
mediated ECE-1b expression. Consistently, we found that Sam68-knockout mice are hypotensive. These
findings are particularly exciting, because clinical studies have identified an E2F binding-site polymorphism in
the ECE-1b promoter and another independent polymorphism in the C-terminal Src kinase (CSK, a major
physiological inhibitor of SFK) gene that are strongly associated with human hypertension. Collectively, our
results and observations reported by other laboratories may have identified a previously unknown mechanism
of BP control that is governed by the Sam68/E2F2–ECE-1b pathway, and deregulation of this pathway may
contribute to BP disorders, including hypertension in humans. However, despite strong evidence indicating that
E2F2 and Sam68 regulates vessel contractility, the Sam68/E2F2–ECE-1b pathway has not been explicitly
linked to BP regulation, and the mechanisms by which Sam68/E2F2 signaling regulates ECE-1b expression
and vascular function remain uncharacterized. The objective of this application is to elucidate the mechanisms
underlying the E2F2-mediated regulation of vascular function and BP. Our central hypothesis is that E2F2
recruits both co-activators and co-repressors (e.g., Sam68) to the ECE-1b promoter, thereby regulating ECE-1
activity and preserving a normal contractile state in arteries. Furthermore, dysregulation of E2F2 and the
E2F2/Sam68 interaction contributes to BP disorders by inducing aberrations in ECE-1 activity and ET-1
biogenesis. We will accomplish our objective with a series of experiments organized under three specific aims:
1) to elucidate the molecular mechanisms by which E2F2 regulates ECE-1b expression; 2) to define the
functional significance of the Sam68/E2F2 signaling in arterial ECs and intact vessels; and 3) to determine the
consequences of dysfunctional Sam68/E2F2–ECE-1b pathway on BP control. We anticipate that the work
proposed in this project will extensively characterize the novel SFK/Sam68–E2F2/ECE-1b pathway in the
regulation of vascular function and BP control, and may potentially reveal new targets for future research into
preventive and t...

## Key facts

- **NIH application ID:** 9908169
- **Project number:** 5R01HL138990-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Yuji Nakada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $568,142
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908169

## Citation

> US National Institutes of Health, RePORTER application 9908169, E2F2 and Vascular Function (5R01HL138990-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9908169. Licensed CC0.

---

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