# Molecular and Cellular Characterization of Primary Endothelial Cells from a Familial Cavernomatosis Patient

## TL;DR

This study isolates and analyzes endothelial cells from a patient with a rare inherited vascular disorder, revealing functional and genetic differences compared to healthy cells.

## Contribution

The novel contribution is the first molecular and cellular characterization of primary endothelial cells from a familial cavernomatosis patient.

## Key findings

- A heterozygous point mutation in CCM1 leads to RNA processing failure and reduced protein expression.
- CCM1 endothelial cells show impaired angiogenesis and cell migration, along with decreased expression of vascular-related genes.
- Vascular impairments are evident even in the heterozygous state, suggesting early predisposition to damage.

## Abstract

Cerebral cavernous malformation (CCM) or familial cavernomatosis is a rare, autosomal dominant, inherited disease characterized by the presence of vascular malformations consisting of blood vessels with an abnormal structure in the form of clusters. Based on the altered gene (CCM1/Krit1, CCM2, CCM3) and its origin (spontaneous or familial), different types of this disease can be found. In this work we have isolated and cultivated primary endothelial cells (ECs) from peripheral blood of a type 1 CCM patient. Differential functional and gene expression profiles of these cells were analyzed and compared to primary ECs from a healthy donor. The mutation of the familial index case consisted of a heterozygous point mutation in the position +1 splicing consensus between exons 15 and 16, causing failure in RNA processing and in the final protein. Furthermore, gene expression analysis by quantitative PCR revealed a decreased expression of genes involved in intercellular junction formation, angiogenesis, and vascular homeostasis. Cell biology analysis showed that CCM1 ECs were impaired in angiogenesis and cell migration. Taken together, the results obtained suggest that the alterations found in CCM1 ECs are already present in the heterozygous condition, suffering from vascular impairment and somewhat predisposed to vascular damage.