Regulation of Pericyte Behavior by Secreted Protein Acidic and Rich in Cysteine

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dc.contributor.advisorBrekken, Rolf A.en
dc.creatorRivera, Lee Benjaminen
dc.date.accessioned2011-02-01T19:36:55Z
dc.date.available2011-02-01T19:36:55Z
dc.date.issued2011-02-01
dc.description.abstractPericytes migrate to newly formed vessels where they induce vessel quiescence and promote vessel stability. Secreted Protein Acidic and Rich in Cysteine (SPARC) is a multifunctional matricellular protein believed to be involved in the regulation of vascular cell migration and proliferation during angiogenesis. We previously found that SPARC-deficient mice exhibited abnormal vascular function and decreased pericyte-associated vessels in an orthotopic model of pancreatic ductal adenocarcinoma (PDAC), suggesting that SPARC regulates pericyte behavior during tumor angiogenesis. Pericyte expression of SPARC was detected in PDAC lesions of P48Cre: LSLKrasG12D: Ink4Alox/lox mice as well as in normal mouse pancreata by indirect immunofluorescence. Primary mouse pericytes were isolated and the following parameters were characterized: proliferation, migration, the ability to induce bEnd.3 cell cord formation, TGFbeta1-induced activity, and TGFbeta1 receptor expression. Here I report that SPARC regulates pericyte migration. I found that SPARC is expressed by pericytes in vivo and confirmed that SPARC-deficient mice have fewer pericyte-associated vessels using a transgenic model of PDAC. Primary pericytes isolated from SPARC-/- mice proliferate faster than their SPARC+/+ counterparts but are less able to induce bEnd.3 cord-formation in vitro. SPARC deficiency also results in defective filopodia and focal adhesion formation and impedes pericyte migration, an effect that is blocked by inhibiting TGFbeta. Furthermore, I demonstrate that SPARC interacts with the TGFbeta1 accessory receptor endoglin in pericytes. In SPARC-deficient pericytes, endoglin aberrantly associates with focal complexes. SPARC deficiency also induces endoglin-mediated, TGFbeta1-induced blockade of pericyte migration, and results in alphaV integrin-mediated activation of TGFbeta1. These results demonstrate that SPARC controls pericyte migration by regulating endoglin and alphaV integrin-mediated TGFbeta1 activity.en
dc.identifier.oclc708581119
dc.identifier.urihttps://hdl.handle.net/2152.5/863
dc.language.isoenen
dc.subjectPancreatic Neoplasmsen
dc.subjectNeovascularization, Pathologicen
dc.subjectOsteonectinen
dc.titleRegulation of Pericyte Behavior by Secreted Protein Acidic and Rich in Cysteineen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2011-01-26
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCell Regulationen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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