The vascularization of engineered tissues is critical to the ultimate success of tissue engineering as an organ replacement therapy. The formation of new capillary vessels in vivo, or angiogenesis, also is linked to the pathogenesis of numerous diseases including cancer, and is regulated by local cues within the tissue microenvironment. The general goal of this RENEWAL proposal is to understand the mechanism by which local extracellular matrix (ECM) properties regulate capillary endothelial cell proliferation, gene expression, and capillary tube morphogenesis required in angiogenesis. The investigator has found that adhesion to ECM cooperates with growth factors to generate not only biochemical, but also mechanical signals that are important in driving capillary endothelial cell function. Studies from the past grant period demonstrated that ECM stiffness and composition could be used to regulate proliferation, gene expression, and capillary tube formation by modulating contractile tension generated by the actin cytoskeleton. In this proposal, the investigator proposes to further investigate the role of these mechanical and adhesive cues in regulating angiogenic behaviors.
Specific Aim 1 will be to investigate the role of ECM stiffness in regulating angiogenesis.
Specific Aim 2 will be to investigate the role of ECM peptide ligands in regulating angiogenesis.
Specific Aim 3 will be to investigate the role of spatial organization of the ECM in regulating angiogenesis. Together, these studies will define the mechanisms by which local structural and mechanical properties within ECM modulate endothelial cell function and capillary morphogenesis, and establish new strategies to promote angiogenesis in native ischemic tissues as well as in ex-vivo engineered tissues.
The formation of new capillary vessels in vivo, or angiogenesis, is a rate limiting challenge in the development of engineered implants for organ replacement. Angiogenesis is also critical to many disease processes, including tumor growth and the establishment of atherosclerosis. This project is designed to develop a better understanding of how angiogenesis is regulated by local adhesive and mechanical cues, such that we may better design future approaches to control the growth of blood vessels in tissues.
| Greco Song, H-H; Rumma, Rowza T; Ozaki, C Keith et al. (2018) Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise. Cell Stem Cell 22:608 |
| Song, H-H Greco; Rumma, Rowza T; Ozaki, C Keith et al. (2018) Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise. Cell Stem Cell 22:340-354 |
| Longchamp, Alban; Mirabella, Teodelinda; Arduini, Alessandro et al. (2018) Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production. Cell 173:117-129.e14 |
| Polacheck, William J; Kutys, Matthew L; Yang, Jinling et al. (2017) A non-canonical Notch complex regulates adherens junctions and vascular barrier function. Nature 552:258-262 |
| Trappmann, Britta; Baker, Brendon M; Polacheck, William J et al. (2017) Matrix degradability controls multicellularity of 3D cell migration. Nat Commun 8:371 |
| Choi, Dongwon; Park, Eunkyung; Jung, Eunson et al. (2017) Laminar flow downregulates Notch activity to promote lymphatic sprouting. J Clin Invest 127:1225-1240 |
| Stevens, Kelly R; Scull, Margaret A; Ramanan, Vyas et al. (2017) In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease. Sci Transl Med 9: |
| Mirabella, T; MacArthur, J W; Cheng, D et al. (2017) 3D-printed vascular networks direct therapeutic angiogenesis in ischaemia. Nat Biomed Eng 1: |
| Nguyen, Duc-Huy T; Gao, Lin; Wong, Alec et al. (2017) Cdc42 regulates branching in angiogenic sprouting in vitro. Microcirculation 24: |
| Alimperti, Stella; Mirabella, Teodelinda; Bajaj, Varnica et al. (2017) Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N-cadherin balance in mural cell-endothelial cell-regulated barrier function. Proc Natl Acad Sci U S A 114:8758-8763 |
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