Program Project Grant:
Integrative Study of Brain Vascular Malformations

From Project 2: Ang1 and Ang2 were localized to the vascular wall of BAVMs. Photomicrographs of serial sections from BAVMs, In-situ hybridization for Ang1 (C, G), and in-situ hybridization for Ang2 (D, H). The lower panel shows higher magnification of the insets in the upper panel. Arrows indicate the endothelial cell layer. The endothelial layer was generally intact (A, B, E, F). BAVM vessels expressed both Ang1 (C, G) and Ang2 (D, H) in the perivascular areas. Bar = 100 µm.

Vascular malformations of the brain account for roughly 10% of stroke syndromes. Clinically, an important subtype is brain arteriovenous malformation (BAVM). For this program project, the unifying theme is a vertically integrated program that can relate clinical characteristics, notably risk of intracranial hemorrhage (ICH) with various aspects of the underlying genetic and cell-to-cell signaling abnormalities. The program project is based on a three-pronged approach: first, the clinical behavior of the disease must be studied to identify natural tendencies likely have biologic underpinning. These clinical behaviors can be associated with genotypic alterations. Second, biologic characteristics of diseased tissue need to be studied to confirm or rule out likely pathways relevant to the human disease. Such pathways need correlation to the clinical behavior of the disease to generate plausible hypotheses. Third, plausible hypotheses must be tested to investigate and identify mechanistic components of relevance to the disease. Once such mechanistic components are identified, strategies to develop therapeutic approaches can be more rationally formulated. In such a triangulation of approaches, there is real promise for translational progress in the innovative therapy of brain vascular malformations.

This program project consists of four projects and three cores: