Primary Cultures of Endothelial and Monocytic Cells Derived from HHT Patients: An Open Window to Unravel the Pathogeniticy of HHT

Mechanism of Disease: $50,000 Research Grant

Carmelo Bernabeu, Ph.D.
Centro de Investgaciones Biologicas, CSIC, Madrid, Spain

 

Dr. Bernabeu’s Cure HHT seed grant has been leveraged to $500,000 through the European Research Agency

 

Blood vessels are lined with endothelial cells that express two proteins known as endoglin and ALK-1. Mutations in endoglin or ALK-1 genes interfere with the expression and function of these proteins in endothelial cells, affecting the vessels network and giving rise to the Hereditary Hemorrhagic Telangiectasia (HHT). Thus, isolation of endothelial cells derived from HHT patients to determine endoglin/ALK-1 levels and activity is crucial to understand how the disease develops. So far, most of the studies have been carried out in endothelial cells from umbilical veins of affected newborns. However, since the prevalence of HHT increases with age, probably these newborn endothelial cells are not a good model system. Instead, endothelial cells from adult patients with known HHT symptoms would be a more appropriate model of choice.

In this project, we propose to isolate and characterize endothelial cells derived from blood samples of HHT patients. The same samples will be used to isolate the blood cells called monocytes, which have been shown to express endoglin, although at lower levels than endothelial cells. Both cell types will be used to determine whether the levels and function of endoglin and ALK-1 are affected in HHT patients and whether there is a correlation between these properties and the severity of the disease in the individual patient. Also, the impact of endoglin or ALK-1 mutations on endothelial gene expression using microarrays, will be assessed. These studies may help to understand the mechanisms of the disease, as well as to design new diagnostic methods.

 

Research Study Update

With Cure HHT’s seed grant, I have received a $500,000 in funding from the European Research Agency,” stated Dr. Bernabeu.

According to Dr. Bernabeu, “Blood vessels are lined with endothelial cells that express two proteins known as endoglin and ALK-1. Mutations in endoglin or ALK-1 genes interfere with the expression and function of these proteins in endothelial cells, affecting the vessels network and giving rise to Hereditary Hemorrhagic Telangiectasia (HHT).

Dr. Bernabeu’s lab isolated and characterized for the first time, circulating endothelial cells derived from blood samples of HHT patients. These cells show functional abnormalities that may explain the vascular lesions of those with HHT. To further investigate the altered function of these cells, his lab analyzed the changes in their gene expression pattern (a sort of fingerprint of the cell). This study has allowed the identification of several genes specifically modified in endothelial cells from HHT patients. The genes affected are involved in different cellular processes relevant to the generation of the vascular lesion. Overall, these represent pioneer studies on the establishment of a culture method to isolate endothelial cells derived from HHT patients. Further studies on the genetic fingerprint of these cells will help to explain the molecular mechanism of the disease, which in turn may contribute to the design of novel therapeutic approaches to cure the disease.

Once a culture method to isolate endothelial cells derived from HHT patients is established, this method can be reproduced by other laboratories and these cells can be used for further biochemical and functional analyses. In addition, studies on the specific genes whose expression is affected in HHT cells are necessary. It is crucial to understand why these genes are disregulated and how the protein’s function is affected in the HHT cell.