title: Intravascular cell delivery device for therapeutic VEGF-induced angiogenesis in chronic vascular occlusion.
abstract: Site specific targeting remains elusive for gene and stem cell therapies in the cardiovascular field. One promising option involves use of devices that deliver larger and more sustained cell/gene payloads to specific disease sites using the versatility of percutaneous vascular access technology. Smooth muscle cells (SMCs) engineered to deliver high local concentrations of an angiogenic molecule (VEGF) were placed in an intravascular cell delivery device (ICDD) in a porcine model of chronic total occlusion (CTO) involving ameroid placement on the proximal left circumflex (LCx) artery. Implanted SMC were retained within the ICDD and were competent for VEGF production in vitro and in vivo. Following implantation, micro-CT analyses revealed that ICDD-VEGF significantly enhanced vasa vasora microvessel density with a concomitant increase in tissue VEGF protein levels and formation of endothelial cell colonies suggesting increased angiogenic potential. ICDD-VEGF markedly enhanced regional blood flow determined by microsphere and contrast CT analysis translating to a functional improvement in regional wall motion and global left ventricular (LV) systolic and diastolic function. Our data indicate robust, clinically relevant angiogenesis can be achieved in a human scale porcine chronic vascular occlusion model following ICDD-VEGF-based delivery of angiogenic cells. This may have implications for percutaneous delivery of numerous therapeutic factors promoting creation of microvascular bypass networks in chronic vaso-occlusive diseases.
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Arun H S
authors.initials: AH
authors.lastname: Kumar
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Martin
authors.affiliation: Division of Cardiovascular Diseases, Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Doyle
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Chien-Ling
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Gopala-Krishnan M
authors.initials: GK
authors.lastname: Pillai
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Mohammed T
authors.initials: MT
authors.lastname: Ali
authors.affiliation: Division of Cardiovascular Diseases, Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Skelding
authors.affiliation: Division of Cardiovascular Diseases, Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Wang
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Birgitta M
authors.initials: BM
authors.lastname: Gleeson
authors.affiliation: Cork Cancer Research Centre, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Saleem
authors.initials: S
authors.lastname: Jahangeer
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Ritman
authors.affiliation: Division of Hematology, Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland; Division of Cardiovascular Diseases, Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA. Electronic address: n.caplice@ucc.ie.
authors.forename: Noel M
authors.initials: NM
authors.lastname: Caplice
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D013552:Swine; D023822:Tissue Engineering; D014652:Vascular Diseases / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D043925:Angiogenesis Inducing Agents; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; Blood flow; Gene therapy; Intravascular stent; Smooth muscle cells