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Cell shape, cytoskeletal mechanics, and cell cycle control in angiogenesisCapillary endothelial cells can be switched between growth and differentiation by altering cell-extracellular matrix interactions and thereby, modulating cell shape. Studies were carried out to determine when cell shape exerts its growth-regulatory influence during cell cycle progression and to explore the role of cytoskeletal structure and mechanics in this control mechanism. When G0-synchronized cells were cultured in basic fibroblast growth factor (FGF)-containing defined medium on dishes coated with increasing densities of fibronectin or a synthetic integrin ligand (RGD-containing peptide), cell spreading, nuclear extension, and DNA synthesis all increased in parallel. To determine the minimum time cells must be adherent and spread on extracellular matrix (ECM) to gain entry into S phase, cells were removed with trypsin or induced to retract using cytochalasin D at different times after plating. Both approaches revealed that cells must remain extended for approximately 12-15 h and hence, most of G1, in order to enter S phase. After this restriction point was passed, normally 'anchorage-dependent' endothelial cells turned on DNA synthesis even when round and in suspension. The importance of actin-containing microfilaments in shape-dependent growth control was confirmed by culturing cells in the presence of cytochalasin D (25-1000 ng ml-1): dose-dependent inhibition of cell spreading, nuclear extension, and DNA synthesis resulted. In contrast, induction of microtubule disassembly using nocodazole had little effect on cell or nuclear spreading and only partially inhibited DNA synthesis. Interestingly, combination of nocodazole with a suboptimal dose of cytochalasin D (100 ng ml-1) resulted in potent inhibition of both spreading and growth, suggesting that microtubules are redundant structural elements which can provide critical load-bearing functions when microfilaments are partially compromised. Similar synergism between nocodazole and cytochalasin D was observed when cytoskeletal stiffness was measured directly in living cells using magnetic twisting cytometry. These results emphasize the importance of matrix-dependent changes in cell and nuclear shape as well as higher order structural interactions between different cytoskeletal filament systems for control of capillary cell growth during angiogenesis.
Document ID
20040173329
Acquisition Source
Legacy CDMS
Document Type
Reprint (Version printed in journal)
Authors
Ingber, D. E.
(Harvard Medical School Boston, MA 02115, United States)
Prusty, D.
Sun, Z.
Betensky, H.
Wang, N.
Date Acquired
August 22, 2013
Publication Date
December 1, 1995
Publication Information
Publication: Journal of biomechanics
Volume: 28
Issue: 12
ISSN: 0021-9290
Subject Category
Life Sciences (General)
Funding Number(s)
CONTRACT_GRANT: CA-45548
CONTRACT_GRANT: CA-55833
CONTRACT_GRANT: HL-33009
Distribution Limits
Public
Copyright
Other
Keywords
Non-NASA Center
NASA Discipline Cell Biology
NASA Program Space Biology
NASA Discipline Number 40-20

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