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Updated: Jul 17, 2026
A Neonatal Heterotopic Rat Heart Transplantation Model for the Study of Endothelial-to-Mesenchymal Transition
Published on: July 21, 2023
Status of the endothelium-derived hyperpolarizing factor pathway in coronary arteries after heterotopic heart
Louis P Perrault1, Marie-Claude Aubin, Olivier Malo
1Research Center, Montreal Heart Institute, Montreal, Quebec, Canada. louis.perrault@icm-mhi.ca
Insights
Heart transplant recipients show impaired endothelium-derived hyperpolarizing factor (EDHF) mediated relaxations, contributing to graft vasculopathy. This study investigated EDHF function and smooth muscle cell hyperpolarization post-transplantation.
Area of Science:
- Cardiovascular Science
- Transplantation Biology
- Vascular Physiology
Background:
- Graft coronary vasculopathy is a major limitation to long-term survival after heart transplantation.
- It involves pathological endothelial activation and loss of vascular wall homeostasis regulation.
- Endothelium-derived hyperpolarizing factor (EDHF) plays a crucial role in vascular health.
Purpose of the Study:
- To evaluate the integrity of EDHF-mediated coronary vascular relaxations after heterotopic heart transplantation.
- To investigate smooth muscle cell hyperpolarization in transplanted coronary arteries.
Main Methods:
- Porcine model of heart transplantation (6 weeks post-transplant).
- Vascular reactivity studies on native and allograft epicardial coronary artery rings.
- Intracellular microelectrode measurements of smooth muscle cell membrane potential.
Main Results:
- Significant decrease in endothelium-dependent relaxations to 5-hydroxytryptamine (5-HT) and bradykinin (BK) in allograft vs. native arteries.
- No alteration in resting membrane potential, depolarization, or hyperpolarization in smooth muscle cells.
- Increased response to cromakalim (K(+)-ATP channel opener) in allograft arteries.
Conclusions:
- Impaired EDHF-mediated relaxations contribute to reduced endothelium-dependent relaxations to BK post-transplantation.
- This EDHF dysfunction may exacerbate endothelial dysfunction, preceding coronary graft vasculopathy development.
- Findings highlight the role of EDHF in maintaining vascular health after heart transplantation.
Background:
After the first year of transplantation, the major limitation to long-term survival is the development of graft coronary vasculopathy, characterized by a pathologic activation of the endothelium with an attendant loss of its regulatory properties on homeostasis of the vascular wall. The present study was designed to evaluate the integrity of coronary vascular relaxations attributed to the endothelium-derived hyperpolarizing factor (EDHF) and to study hyperpolarization of smooth muscle cells after heterotopic heart transplantation.
Methods:
Six weeks after heart transplantation in a porcine model, vascular reactivity studies of control, native and allograft epicardial coronary artery rings were performed in standard organ chamber experiments. Moreover, membrane potential measurements were made with intracellular microelectrodes in rings of native and allograft coronary arteries.
Results:
There was a significant decrease in endothelium-dependent relaxations to 5-hydroxytryptamine (5-HT), high doses of bradykinin (BK) alone and BK plus N-omega-nitro-L-arginine (L-NNA) in rings from allograft compared to native, whereas the variation was significantly increased in response to cromakalim, a K(+)-ATP channel opener. Electrical and mechanical recordings showed no alteration in the resting membrane potential of smooth muscle cells, depolarization during contraction to prostaglandin F(2alpha) (PGF(2alpha)), or hyperpolarization in the presence of BK + L-NNA in rings of allograft vs native.
Conclusions:
In this swine model of heart transplantation, part of the reduction in endothelium-dependent relaxations to BK may be attributed to an alteration in the activity of EDHF. This impairment of EDHF-mediated relaxations may compound the endothelial dysfunction preceding the development of coronary graft vasculopathy.
