The Role of Podosomes in Cerebrovascular Integrity and Intracranial Aneurysm

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PROJECT SUMMARY An intracranial aneurysm (IA) is a focal dilatation of an arterial blood vessel in the brain. The rupture of IA causes subarachnoid hemorrhage (SAH), which is the most devastating form of stroke. Due to aneurysmal SAH, around one-third of aneurysm patients will die before reaching the hospital and half of the survivors will never return to independent living. In the United States, around 30,000 people annually suffer a ruptured IA. Unfortunately, there are no drugs available to treat IA except for invasive surgical options, which produce much higher health care costs and are associated with multiple hospitalizations. Therefore, new therapeutic targets are urgently needed as non-invasive alternatives to prevent aneurysmal rupture. However, such attempts have been greatly impeded by a lack of knowledge about the pathogenic and cellular mechanisms that contribute to IA disease. High wall shear stress (HWSS) directly acts on the endothelium of vascular wall as a result of blood flow and is a well- known clinical risk factor for IA disease. The casual role of HWSS in IA pathogenesis has been validated in multiple animal models. However, the molecular basis for HWSS-induced IA development is largely unknown. Interestingly, we observed that HWSS stimulates the assembly of podosomes in the endothelial cells that are subcellular organelles with the ability to degrade extracellular matrix. Based on our preliminary data, we hypothesize that podosome formation and function contributes to IA development and growth under HWSS conditions, and anti-podosome therapy may provide a beneficial effect on IA disease. To test this hypothesis, we will carry out the following specific aims: 1) dissect the molecular mechanisms of HWSS-induced podosome formation and maturation; 2) determine the role of HWSS-induced podosome formation and function in cerebrovascular integrity and IA development and growth. To our knowledge, our proposal is the first to connect podosomes to cerebrovascular integrity, providing a novel mechanism for IA pathogenesis and highlighting a unique anti-podosome therapy for IA disease. Importantly, podosome formation and function can be effectively blocked by SRC kinase inhibitors, which have been intensively developed, including multiple FDA-approved drugs. This fact also makes our study of translational potential for IA disease, or for many other diseases due to the loss of vascular integrity.