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Overview of Research Studies
What is the role of fibronectin fibrils in vivo?
Hocking, D.C., Titus, P.A., Sumagin, R., and Sarelius, I.H. (2008) Extracellular matrix fibronectin mechanically couples skeletal muscle contraction with local vasodilation, Circ. Res. 102:372-379. The flow of blood to skeletal muscle is tightly coupled to metabolic activity. Here, we used intravital microscopy to show that fibronectin fibrils in connective tissue matrices transduce signals from contracting skeletal muscle to local blood vessels to increase blood flow. This study revealed a novel paradigm in which tensile forces from contracting skeletal muscle expose the matricryptic site in FNIII-1 which in turn, signals a nitric oxide-dependent increase in arteriolar diameter. These studies provided the first evidence that extracellular fibronectin fibrils play a dynamic role in regulating arteriolar responses in vivo.
Where is the cryptic heparin-binding site in FNIII-1 and does it mediate the increase in cell growth? Does the cell growth response to fibronectin require an increase in cell area?
Gui, L., Wojciechowski, K., Gildner, C.D., Nedelkovska, H., and Hocking, D.C. (2006) Identification of the heparin-binding determinants within fibronectin repeat III1: Role in cell spreading and growth. J. Biol. Chem. 281:34816-34825. Our earlier studies indicated that many of the effects of ECM fibronectin on cell function are mediated by a matricryptic site in the first type III repeat (FNIII-1). In this study, we localized the growth-promoting activity of the matricryptic site in FNIII-1 to a cluster of basic, heparin-binding amino acid residues. We showed that the matricryptic site also stimulates cell spreading, but that increased cell area in response to extracellular matrix fibronectin is not necessary for the proliferation response.
Does fibronectin contribute to the mechanical properties of tissues?
Gildner, C.D., Lerner, A.L., and Hocking, D.C. (2004) Fibronectin matrix polymerization increases tensile strength of model tissue. Am. J. Physiol. Heart and Circ. Physiol. 287:H46-H53. Most organs and tissues in the body are subjected to mechanical stresses and strains. Thus, one of the challenges to tissue engineering involves identifying and optimizes the critical structural and mechanical factors that contribute to the mechanical properties of load-bearing tissues. In this study, we showed that addition of fibronectin to engineered tissue constructs enhances the mechanical properties of these artificial tissues. The increase in mechanical strength was dependent on fibronectin polymerization, demonstrating that the three-dimensional organization of the extracellular matrix is an important determinant in tissue strength.
What is the role of ECM fibronectin in cell migration?
Hocking, D.C. and Chang, C. H. (2003) Fibronectin matrix polymerization regulates small airway epithelial cell migration. Am. J. Physiol. 285:L169-179. The restoration of the airway epithelial barrier following injury involves the migration of epithelial cells at the leading edge of the wound over a fibronectin-containing provisional matrix. In this study, we used an in vitro model of wound healing to distinguished the effects of soluble and extracellular matrix fibronectin on the migration of small airway epithelial cells. Our findings demonstrated that small airway epithelial migration requires active fibronectin matrix polymerization Here, we demonstrated a stimulatory role for fibronectin’s matricryptic III-1 site in epithelial cell motility.
How does the ECM form of fibronectin affect cell function?
Hocking, D.C. and Kowalski, K. (2002) A cryptic fragment from fibronectin’s III-1 module localizes to lipid rafts and stimulates cell growth and contractility. J. Cell Biol. 158:175-184. The mechanisms by which the ECM form of fibronectin increased cell growth and contractility was unknown. We hypothesized that as cells remodel their fibronectin matrix, the exposure of new epiopes may serve to initiate responses that are unique to matrix fibroencitn. Using a panel of recombinant fibronectin fragments, this study was the first to show that a portion of extracellular matrix fibronectin partitions into caveolin-containing lipid rafts and differentially regulates cytoskeletal organization and growth, in part, through the exposure of a matricryptic site within the conformationally-labile III-1 module.
Contact Us
Denise C. Hocking, Ph.D.
University of Rochester
School of Medicine and Dentistry
Box 711
601 Elmwood Avenue
Rochester, NY 14642
Telephone: 585-273-1770
Fax: 585-273-2652
