Vascular Biology

Research in the Vascular Biology theme focuses on the mechanisms of endothelial function and the relationships between endothelial function and vascular inflammation. The vascular biology theme has important links with the genetics theme and aspects of redox signalling that are also important in the myocardial biology theme.

The work on endothelial function investigates the regulation of endothelial nitric oxide synthase (eNOS) by the cofactor tetrahydrobiopterin (BH4). Recent findings include the identification of BH4 as an important determinant of endothelial function, vascular remodelling after injury and endothelial cell repopulation and growth. Translational proof-of principle clinical studies are underway, focusing on pharmacokinetic and mechanistic aspects of drugs that target eNOS regulation. These clinical studies incorporate non-invasive imaging of vascular function and structure, using both ultrasound and state-of-the art MRI techniques that provide biological and statistical power through sophisticated quantitative phenotypes. A further unique strength is the combination of clinical non-invasive assessment with biochemical, molecular genetic and functional readouts determined directly from vascular tissue samples obtained from patients recruited into clinical trials prior to CABG surgery.

The relationship between endothelial function, oxidative stress and inflammation in atherosclerosis is explored in models of altered chemokine signalling and macrophage function. This programme incorporates a number of important synergies, including interactions between basic macrophage cell and molecular biology, experimental gene therapy studies, mouse models of vascular disease, and experimental and molecular imaging. Furthermore, clinical and translational studies in coronary artery disease and stroke build on the platforms established in the inflammation programme. These include novel imaging techniques, biomarker identification and biological therapeutics.

Vascular biology provides functional genomics and clinical phenotyping support to the Genetics Theme. In turn, resources from the Genetics Theme, such as the HTO study and the PROCARDIS study, will enable potential biological candidates to be tested with uniquely high power in relation to both quantitative intermediate phenotypes and clinical endpoints.

The cross cutting scientific interest in nitric oxide/redox signalling and inflammation will provide a major focus for both vascular and myocardial biology, and associated clinical/translational themes. The redox signalling and vascular inflammation programmes are anticipated to yield significant early advances in translational studies based on proof-of-principle in mouse models of vascular disease, and will synergise with clinical studies in molecular imaging and biomarker identification in coronary artery disease and stroke. The mouse model and clinical phenotyping strengths will together enable rapid evaluation of new genes identified in PROCARDIS and other large-scale genetic studies of CAD.