Title:
Role of shear stress in angiopoietin-2-dependent neovascularization: implications in occlusive vascular disease and atherosclerosis

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dc.contributor.advisor Jo, Hanjoong
dc.contributor.author Tressel, Sarah Lynne en_US
dc.contributor.committeeMember McIntire, Larry
dc.contributor.committeeMember Nie, Shuming
dc.contributor.committeeMember Taylor, Robert
dc.contributor.committeeMember Weyand, Cornelia
dc.contributor.department Biomedical Engineering en_US
dc.date.accessioned 2008-06-10T20:42:55Z
dc.date.available 2008-06-10T20:42:55Z
dc.date.issued 2008-03-06 en_US
dc.description.abstract Neovascularization, or the formation of blood vessels, is important in both normal physiological processes as well as pathophysiological processes. The main players in neovascularization, endothelial cells (EC), are highly influenced by hemodynamic shear stress and this may play an important role in neovascularization. Two typical types of shear stress found in the vascular system are a unidirectional laminar shear stress (LS) found in straight regions and a disturbed, oscillatory shear stress (OS) found at branches or curves. At the cellular level, LS is thought to promote EC quiescence whereas OS is thought to promote EC dysfunction. Oscillatory sheared EC are pro-proliferative, pro-migratory, and secrete growth factors, all functions important in neovascularization. There are several diseases that involve both disturbed shear stress and neovascularization, such as atherosclerosis, aortic valve disease, and occlusive vascular disease. In these pathophysiological scenarios fluid shear stress may provide a driving force for neovascularization. Therefore, we hypothesized that oscillatory shear stress promotes greater neovascularization compared to unidirectional laminar shear stress through the secretion of angiogenic factors, which play a physiological role in neovascularization in vivo. To test this hypothesis, we first performed tubule formation and migration assays, two important functions in neovessel formation. We found that OS promotes greater tubule formation and migration of EC as compared to LS and this was mediated through secreted factors. Using gene and protein array analysis, we identified Angiopoietin-2 (Ang2) as being upregulated by OS compared to LS in EC. We found that inhibiting Ang2 blocked OS-mediated tubule formation and migration and that LS-inhibited tubule formation could be rescued by addition of Ang2. In addition, Ang2 was found to be upregulated at sites of disturbed flow in vivo, implicating a physiological role for Ang2. To further investigate the physiological role of Ang2 in neovascularization, we examined the effects of inhibiting Ang2 in a mouse model of hindlimb ischemia, which involves both disturbed flow and neovascularization. We found that Ang2 was upregulated in the ischemic adductor muscle suggesting that it plays a role in recovery during hindlimb ischemia. In addition, we found that inhibiting Ang2 decreased blood flow recovery. Ang2 inhibition resulted in decreased smooth muscle cell coverage of vessels as well as decreased macrophage infiltration. These findings suggest that Ang2 promotes blood flow recovery through the recruitment of smooth muscle cells and formation of collaterals, as well as the recruitment of macrophages that secrete important growth factors and help degrade the extracellular matrix in order for neovascularization to occur. In conclusion, this work illustrates the shear stress regulation of neovessel formation through the expression of Ang2, and the role of Ang2 in neovascularization in vivo. By understanding how angiogenic factors are regulated and what role they play in vivo, we can better understand human disease and develop important therapeutic targets. en_US
dc.description.degree Ph.D. en_US
dc.identifier.uri http://hdl.handle.net/1853/22646
dc.publisher Georgia Institute of Technology en_US
dc.subject Hindlimb ischemia en_US
dc.subject Endothelial cells en_US
dc.subject Arteriogenesis en_US
dc.subject Shear stress en_US
dc.subject Angiopoietin-2 en_US
dc.subject Angiogenesis en_US
dc.subject.lcsh Vascular endothelium
dc.subject.lcsh Blood-vessels Growth
dc.subject.lcsh Shear flow
dc.subject.lcsh Neovascularization
dc.title Role of shear stress in angiopoietin-2-dependent neovascularization: implications in occlusive vascular disease and atherosclerosis en_US
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.advisor Jo, Hanjoong
local.contributor.corporatename Wallace H. Coulter Department of Biomedical Engineering
local.contributor.corporatename College of Engineering
relation.isAdvisorOfPublication 7eb8fb49-de34-4fc6-aea8-80b31a2a2be8
relation.isOrgUnitOfPublication da59be3c-3d0a-41da-91b9-ebe2ecc83b66
relation.isOrgUnitOfPublication 7c022d60-21d5-497c-b552-95e489a06569
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