Person:
Botchwey, Edward A.

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    Therapeutic Angiogenesis and Bone Regeneration with Natural and Synthetic Small Molecules
    (Georgia Institute of Technology, 2013-06-11) Botchwey, Edward A.
    Endothelial cells play significant roles in conditioning the environment in local tissues after injury by the production and secretion of angiocrine factors. At least two distinct subsets of leukocytes, CD45+ CD11b+ Ly6C+Gr1+CX3CR1lo inflammatory monocytes (IM) and CD45+CD11b+Ly6CGr1-CX3CR1hi anti-inflammatory monocytes (AM), respond differentially to these angiocrine factors and promote pathogen/debris clearance and angiogenesis/wound healing, respectively. Our laboratory is currently investigating how local sphingosine 1-phosphate receptor 3 (S1P3) agonism recruits AM to remodeling vessels. We employ micron and nanoscale biomaterials to deliver FTY720, a S1P1/3 agonist, to inflamed and ischemic tissues, to reduce in pro-inflammatory cytokine secretion and an increase in regenerative cytokine secretion. The altered balance of cytokine secretion results in a reduction in inflammatory monocyte recruitment and an increase in anti-inflammatory CX3CR1hi monocyte recruitment to a pro-regenerative perivascular niche. Increased S1P3 expression and activation on AM resulted in significantly enhanced SDF-1α chemotaxis over IM. AM recruitment also enhanced arteriolar diameter expansion and increased length density of the local vasculature: classic signs of vascular remodeling. This work establishes a role for S1P receptor signaling in the local conditioning of tissues by angiocrine factors that preferentially recruit regenerative monocytes that can enhance healing outcomes, bone tissue regeneration, and biomaterial implant functionality.
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    Harnessing systems biology approaches to engineer functional microvascular networks
    (Georgia Institute of Technology, 2010) Sefcik, Lauren S. ; Wilson, Jennifer L. ; Papin, Jason A. ; Botchwey, Edward A.
    Microvascular remodeling is a complex process that includes many cell types and molecular signals. Despite a continued growth in the understanding of signaling pathways involved in the formation and maturation of new blood vessels, approximately half of all compounds entering clinical trials will fail, resulting in the loss of much time, money, and resources. Most pro-angiogenic clinical trials to date have focused on increasing neovascularization via the delivery of a single growth factor or gene. Alternatively, a focus on the concerted regulation of whole networks of genes may lead to greater insight into the underlying physiology since the coordinated response is greater than the sum of its parts. Systems biology offers a comprehensive network view of the processes of angiogenesis and arteriogenesis that might enable the prediction of drug targets and whether or not activation of the targets elicits the desired outcome. Systems biology integrates complex biological data from a variety of experimental sources (-omics) and analyzes how the interactions of the system components can give rise to the function and behavior of that system. This review focuses on how systems biology approaches have been applied to microvascular growth and remodeling, and how network analysis tools can be utilized to aid novel pro-angiogenic drug discovery.
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    Mechanistic Interrogation of Phthalimide Neovascular Factor 1 using Network Analysis Tools
    (Georgia Institute of Technology, 2007-10) Wieghaus, Kristen A. ; Gianchandani, Erwin P. ; Brown, Milton L. ; Papin, Jason A. ; Botchwey, Edward A.
    Neovascularization is essential for the survival and successful integration of most engineering tissues after implantation in vivo. The objective of this study was to elucidate possible mechanisms of phthalimide neovascular factor 1 (PNF1), a new synthetic small molecule proposed for therapeutic induction of angiogenesis. Complementary deoxyribonucleic acid microarray analysis was used to identify 568 transcripts in human microvascular endothelial cells (HMVECs) that were significantly regulated after 24-h stimulation with 30 lM of PNF1, previously known as SC-3–149. Network analysis tools were used to identify genetic networks of the global biological processes involved in PNF1 stimulation and to describe known molecular and cellular functions that the drug regulated most highly. Examination of the most significantly perturbed networks identified gene products associated with transforming growth factor-beta (TGF-b), which has many known effects on angiogenesis, and related signal transduction pathways. These include molecules integral to the thrombospondin, plasminogen, fibroblast growth factor, epidermal growth factor, ephrin, Rho, and Ras signaling pathways that are essential to endothelial function. Moreover, real-time reversetranscriptase polymerase chain reaction (RT-PCR) of select genes showed significant increases in TGFb- associated receptors endoglin and beta glycan. These experiments provide important insight into the pro-angiogenic mechanism of PNF1, namely, TGF-b-associated signaling pathways, and may ultimately offer new molecular targets for directed drug discovery.