Grant: CIHR-ICRH Travel Awards - General pool

Cerebral small vessel disease (CSVD) is a condition that affects the smallest blood vessels in the brain and is responsible for a quarter of all stroke-related deaths. The damage caused by CSVD to these blood vessels progresses silently, and currently, there are no treatments that target the underlying mechanisms of the disease. However, recent studies have implicated a group of genes called "matrisome" genes, which are involved in producing the extracellular matrix (ECM), in the genetic basis of CSVD. One particular gene of interest is FOXF2, which has been found to be associated with CSVD and stroke in humans. To investigate the role of FOXF2 in vascular stability, we use animal models, specifically zebrafish. In zebrafish, foxf2 is expressed in brain pericytes, specialized cells that play a crucial role in supporting the health and function of blood vessels in the brain. Our results show that zebrafish with mutations in the foxf2 gene have fewer brain pericytes during early development, and this deficiency persists as they grow. As a result, many brain vessels lack support. Additionally, the few pericytes that are present in these mutants show abnormal changes in their shape and an increased risk of cell death, further compromising the integrity of the brain's blood vessels. We have also focused on downstream genes regulated by foxf2. One gene of interest, called loxl2, when mutated, shows similar reductions in pericytes as observed in the loss of foxf2. These findings highlight the importance of matrix remodeling genes in the development of CSVD as loxl2 is important for ECM integrity. Taken together, these results underscore the critical role of developmental processes in CSVD. Understanding the relationship between foxf2 and vascular stability in the developing brain has the potential to pave the way for therapeutic strategies aimed at reducing the burden of stroke over a person's lifetime. By targeting these mechanisms, we hope to develop treatments that can prevent or alleviate the progression of CSVD and improve the overall health outcomes for individuals at risk of stroke.