Genetic Causes and Therapeutic Interventions in Vascular Malformations

Vascular malformations are vessels that improperly formed during fetal development. They can include different types of vessels such as arteries, veins, and lymphatics and are termed arteriovenous, venous, and lymphatic malformations, respectively. Overall, vascular malformations affect 1.2%-1.5% of the general population and range from a prevalence of 0.1% for lymphatic malformations, 0.3% for arteriovenous malformations, and 1% for venous malformations. Vascular malformations can cause complications, some of which can be life-threatening. These can include severe hemorrhaging, life-threatening infections, clotting abnormalities, deep vein thrombosis, pain, and difficulties with ambulation. Despite these severe complications, there is no Food and Drug Administration (FDA)-approved treatment for vascular malformations. Development of effective, biologically targeted therapies is sorely needed, but is hampered by limited understanding of vascular malformation genetics and disease biology.

Mutations in several genes have been discovered in patients with vascular malformations. A subset of patients have germline mutations, that is, the mutation is present in every cell. However, many more patients with vascular malformations have somatic mutations, where the mutations are only present in the malformation tissues, specifically the endothelial cells, or the cells that line the blood vessels. Interestingly, there are several genes that seem to be commonly mutated in patients with different subtypes of vascular malformations.

Our laboratories have successfully isolated abnormal vascular malformation endothelial cells in different subtypes of vascular malformations. Using whole exome sequencing, a technology that allows us to analyze the coding sequences of all genes, we have been able to identify reported, as well as novel, unreported mutations, thus validating our approach of using malformation endothelial cells and whole exome sequencing to understand the genetic abnormalities in vascular malformations.

We hypothesize that isolated affected vascular malformation endothelial cells can be used to identify causative genetic mutations and understand how the mutations affect vascular malformation pathology and therapeutic response.

Aim 1: Identification of pathogenic mutations in endothelial cells isolated from vascular malformations.

We will collect a wide variety of malformations from patients with lymphatic malformations, venous malformations, and arteriovenous malformations. We will isolate and characterize the endothelial cells from the samples. We will then use whole exome sequencing to identify novel and known genetic mutations in the endothelial cells. The goal is to understand the genetic causes of vascular malformations.

Aim 2: Determine the effects of pathological variants on therapeutic responses in vascular malformations.

We hypothesize that the specific genetic mutation in the vascular malformation endothelial cells influence therapeutic responses. We will use cell culture and mouse models to determine how different genetic mutations affect the response of the endothelial cells of the malformations to drug treatment. Data gathered from these studies will identify more possible drugs that can be used to treat vascular malformation patients and help guide us in deciding which drug may be the best for each individual patient.

Aim 3: Determine the effects of pathogenic gene variants on vascular malformation pathogenesis.

We hypothesize that specific changes in the DNA of genes or mutations influence the development of vascular malformations. We would like to understand how different mutations within the same gene can give rise to different types of malformations and how the mutations affect the endothelial cells' ability to form a normal vessel resulting in a vascular malformation development. This information will give us insight into how the vascular system develops and allow us to predict, based on genetic mutations, what kind of disease processes that can develop. Understanding this information is necessary to guide the development of biologically targeted therapies. This aim will give us insights not just into vascular malformations, but in other disease processes in which there is abnormal blood vessels, e.g., too much, like cancer, or not enough blood vessels, in heart attacks and strokes.