Role of Endoglin in HHT and High Output Heart Failure
Simon Tual-Chalot, PhD, is a Post Doctoral Associate at Newcastle University working under the direction of Dr. Helen Arthur, Professor of Cardiovascular Biology. In 2015, Dr. Tual-Chalot was awarded a $30,000 Young Investigator Grant by Cure HHT.
Proposed Research Summary
Endoglin is a protein that is found on the surface of the cells that line the blood vessels. When this protein is missing from these lining cells, known as enothelial cells, the heart enlarges rapidly to form a more muscular and bigger heart which puts undue strain on the heart and can lead to high output cardiac failure which is associated with HHT.
The evidence so far suggests that endoglin is required in the blood vessels to regulate vascular resistance which is important for normal heart function. Dr. Tual-Chalot’s project used a mouse model to permit depletion of endoglin in endothelial cells to investigate how endoglin maintains the adult vasculature to protect against high output heart failure (HOHF).
Dr. Tual-Chalot’ research will:
- Aim 1 – Establish the timing and extent of the HOHF phenotype following endoglin depletion
- Aim 2 – Determine the role of endoglin in vasoregulations of resistance arteries
- Aim 3 – Examine changes in vessel architecture following loss of endoglin.
This knowledge will help to develop treatments for HHT patients with this heart condition.
Research Study Update
Aim 1 – Dr. Tual-Chalot concluded that the loss of endoglin in endothelial cells leads to progressive pathological cardiac failure that is not driven by anaemia or hypoxia. Changes in the heart are seen within 3 weeks of endoglin loss, the phenotype gradually worsens and without intervention the outcome is ultimately fatal.
Aim 2 – It was determined that circulating levels of vasoregulators NO and Endothelin-1 were unchanged following endoglin depletion suggesting these vasoregulators do not contribute to the HOHF phenotype. Circulating levels of Sol-Eng were reduced (as expected) and could potentially contribute to the phenotype. Inhibition of VEGF signalling through VEGFR2 protected against development of the HOHF phenotype.
Aim 3 – Dr. Tual-Chalot’s research discovered that no shunts or AVMs were detected following endothelial specific endoglin depletion, suggesting that AVMs are not the cause of the heart failure.
Future Plans – Dr. Tual-Chalot characterized the HOHF phenotype in Eng-iKOe mice and found this is not due to anaemia or AVMs, but appears to be due to changes in vasoregulation. Therefore, the focus of the next phase of his research will move to the role of endoglin in vasoregulation and vascular resistance. In particular understanding the rescue of the heart failure phenotype by inhibition of VEGF signalling (through VEGFR2) will provide a major focus of research moving forwards.
Dr. Tual-Chalot’s research showed the essential role of endoglin in the maintenance of adult cardio-vasculature and his novel findings were presented at the International HHT Scientific Conference in Dubrovnik, Croatia in June 2017 (Abstracts; Executive Summary)