Abstract Body: Introduction: Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal severe genetic disease, presenting hyperextensible skin, hypermobile joints, and fragility blood vessels leading to life-threatening ruptures or aneurysms. vEDS is caused by heterozygous mutations located in the gene encoding type III procollagen (COL3A1), a major component of arterial wall that affects the integrity of connective tissues. However, the biological mechanisms through COL3A1 mutations influence arterial disorder is not fully understood.
Methods: To conduct our investigation, we identified 5 vEDS patients at Stanford Hospital. We employed Single-Nuclei Multiome on vascular tissue from one patient with severe aneurysm. We generated five patient-specific iPSC lines and differentiated them into endothelial cells (ECs). We assessed endothelial functions, including angiogenesis, LDL uptake, and NO release, comparing patient-derived ECs to healthy controls. Bulk RNA sequencing was conducted to analyze iPSC-ECs and compare them with CRISPR-generated isogenic controls.
Results: Our finding reveals that endothelial cells dysfunction in single-cell chromatin accessibility and gene expression profiling of vEDS patient’s vascular tissue. vEDS iPSC-ECs exhibit impaired capacity of angiogenesis, LDL uptake, and NO release compared to healthy controls. Transcriptional profiling indicates increased vascular permeability associated with the upregulation of MMP2/MMP9, suggesting their role in endothelial barrier disruption. Genome-edited isogenic iPSC-ECs restore endothelial function, pointing to a potential corrective mechanism.
Conclusion: Endothelial cells regulate vascular permeability by controlling the exchange between the blood and surrounding tissues. Increased vascular permeability, leading to the leakage of fluids and proteins from blood vessels, is implicated in the development and rupture of aneurysms, representing a potential mechanism underlying EC dysfunction in vEDS patients. We anticipate that our findings will contribute to a better understanding of vEDS pathology and pave the way for therapeutic strategies aimed at restoring vascular function and improving patient outcomes.