William Young

Research Interests

Integrative Pathophysiology of vascular malformations in the brain with special emphasis on development and rupture risk.

Research Summary

Brain arteriovenous malformations (BAVMs) are a rare but treatable cause of stroke from bleeding into the brain. A unifying theme of our group's studies is defining what the risks of neurologic damage are from both the natural history of the disease as well as from treatment of the disease. By knowing the balance between natural history and treatment risks in different subgroups of patients, more rational care can be offered to patients and new therapeutic approaches are developed. Three sets of studies are described.

First, by examining surgical specimens with the tools of molecular biology, the pathways associated with the genesis of human vascular malformations can be studied. Examples of these malformations include BAVMs, cavernous malformations, dural arteriovenous fistulas, and aneurysms. By use of cell culture systems and the development of small animal models, mechanistic studies can be undertaken to unravel the missteps in development or maturation, which result in the human disease. From these studies, insights into better treatment strategies can be undertaken. A key system of interest is the Tie-2 / Angiopoietin signaling pathway.

Second, computational modeling of the cerebral circulation is a method to extend our limited ability to interrogate the cerebral circulation with conventional means. In humans, there are certain key physiological signals that cannot be measured directly. Sheer stress at the endothelial surface is one such potent force in vascular homeostasis and adaptation. Modern magnetic resonance imaging of the human cerebral circulation can yield information about flow dynamics and geometry, which can then be used to estimate sheer forces likely to be present at the endothelial surface. By the development of computational models, local pertubations in sheer forces can be correlated with morphologic abnormalities of the circulation, such as cerebral aneurysms. It is often possible to take incomplete sets of experimental data and generate likely hypotheses to further test. Further, theoretical modeling of brain arteriovenous malformations BAVM rupture risk can be used to improve selection of variables to develop for use in risk stratification purposes in clinical trials. A long-term goal of this line of inquiry is to eventually develop "patient-specific" physiologic models that can be used in conjunction with modern anatomic imaging for treatment planning and outcome assessment.

Third, BAVMs offer an opportunity to investigate how the cerebral circulation adapts to chronic arterial hypotension, a final common pathway for many kinds of brain injury. High flow though a BAVM can induce low blood pressure in surrounding normal areas of brain. We are performing a set of clinical research studies that examine the mechanisms by which normal brain can adapt to chronic decreased perfusion pressure. Preliminary evidence suggests involvement of some change in endothelial or neuronal nitric-oxide signaling. This work has been expanded to examine other clinical states, which may share aspects of the same pathophysiology, such as cerebral hyperperfusion after percutaneous transluminal angioplasty and stenting of the arterial supply to the brain.

Selected Publications

C.Z. Lee, J.S. Yao, W. Zhai, Y, Huang, W. Liu, E. Lin, B.J. Guglielmo, G.Y. Yang, W.L. Young. Dose-response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation. J Cereb Blood Flow Metab, 2006.

Y. Chen, L. Pawlikowska, J.S. Yao, F. Shen, W. Zhai, A.S. Achrol, M.T. Lawton, P.Y. Kwok, G.Y. Yang, W.L. Young. Interleukin-6 involvement in brain arteriovenous malformations. Ann Neurol, 2006.

A.S. Achrol, L. Lawlikowska, C.E. McCulloch, K.Y.T. Poon, C. Ha, J.G. Zaroff, S.C. Johnston, C. Lee, M.T. Lawton, S. Sidney, D. Marchuk, P.Y. Kwok, W.L. Young. TNFa-238>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arterioveous malformations. Stroke, 2006.

J.G. Zaroff, L. Pawlikowska, J.C. Miss, S. Yarlagadda, C. Ha, A.S. Achrol, P.Y. Kwok, C.E. McCulloch, M.T. Lawton, N.U. Ko, W.S. Smith, W.L. Young. Adrenoceptor polymorphisms and the risk of cardiac injury and dysfunction after subarachnoid hemorrhage. Stroke, 2006.

Y. Zhu, M.T. Lawton, R. Du, Y. Shwe, F. Shen, W.L. Young, G.Y. Yang. Expression of hypoxia-inducible factor-1 and vascular endothelial growth factor in response to venous hypertension. Neurosurgery, 2006.