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The Roles of the High and Low Molecular Weight Isoforms of Fibroblast Growth Factor 2 in Ischemia-Induced Revascularization

Adeyemo, Adeola T

Abstract Details

2016, PhD, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
Cardiovascular diseases are the underlying cause for majority (>30%) of deaths worldwide. They include coronary heart disease and peripheral artery disease, conditions characterized by limited blood flow and inadequate oxygenation. Treatment strategies include management of symptoms and risk factors, reduction of oxygen demand and surgical revascularization to increase circulation. Therapeutic revascularization is a potential alternative for patients who are poor candidates for these interventions due to advance disease or co-morbidities. Revascularization involves the genetic or pharmacologic stimulation of vascular growth processes to facilitate tissue perfusion and promote functional recovery. Adaptive vascular growth occurs via capillary vessel growth (angiogenesis) and growth or remodeling of collateral arteries (arteriogenesis). Delivery of angiogenic factors such as fibroblast growth factor 2 (FGF2) to ischemia tissues can stimulate blood vessel growth. FGF2 consists of two classes of protein isoforms generated from alternative translation of the Fgf2 gene, high molecular weight (HMW) FGF2, and low molecular weight (LMW) FGF2. Proof-of-concept studies in animal models of chronic ischemia provided evidence for the therapeutic potential of exogenous LMW FGF2. This promise, however, did not translate into successful clinical use. Currently, the functions of the endogenous FGF2 isoforms in ischemia-induced revascularization are not well understood. Elucidating the function(s) of the FGF2 isoforms in vascular growth is of great clinical importance and may lead to the development of novel pharmacological therapies for ischemic diseases. Mice with a targeted deletion of all FGF2 isoforms (Fgf2-/-), HMW FGF2 (FGF2 LMW-only) and LMW FGF2 (FGF2 HMW-only) were employed to identify the distinct role(s) of the FGF2 isoforms in chronic ischemia. Revascularization was evaluated in mice subjected to chronic hindlimb ischemia using measures of limb function, tissue viability, and vessel growth. FGF2 HMW-only mice had a faster recovery of limb function compared to wildtypes. Fgf2-/- and FGF2 LMW-only mice, however, had a significantly slower recovery of function. Additionally, no limb necrosis was detected in FGF2 HMW-only mice while Fgf2-/- and FGF2 LMW-only mice had significant necrosis of their ischemic limbs. The early recovery of limb function in FGF2 HMW-only limbs was preceded by improved revascularization (angiogenesis and arteriogenesis). Vessel growth was significantly decreased in FGF2 LMW-only muscles and not different from wildtypes in Fgf2-/- mice, indicating that the presence of LMW FGF2 inhibited vascular growth. The effect of the HMW FGF2 isoforms on revascularization and protection from ischemic injury was not associated with activation of FGF receptor (FGFR). Angiogenesis-related proteins including IGFBP-3, IGFBP-10 and CX3CL1 were increased in HMW FGF2-only muscles and are likely involved in the protective effect of HMW FGF2. Another possible mechanism mediating HMW FGF2-induced recovery from ischemic damage is myocyte regeneration. Preliminary results indicate the presence of amplified satellite cell activation in HMW FGF2 muscles, which was represented by upregulation of Pax7 expression. Pax7 expression was coupled with increased expression of the myoblast differentiation genes, Myogenin and MRF4. Together, these data, for the first time, show that the HMW FGF2 isoforms had a beneficial role in salvaging skeletal muscle from ischemic injury. This dissertation uncovered a biological role for HMW FGF2 isoforms in vascular growth. Though the mechanisms that mediate this function of HMW FGF2 isoforms remain to be thoroughly characterized, this dissertation provides significant and novel evidence for the role of the FGF2 HMW isoforms in ischemia-induced revascularization and preservation of muscle function.
Jo El Schultz, Ph.D. (Committee Chair)
James B. Hoying, Ph.D. (Committee Member)
Walter Jones, Ph.D. (Committee Member)
Ronald Millard, Ph.D. (Committee Member)
Daria Narmoneva, Ph.D. (Committee Member)
346 p.

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Citations

  • Adeyemo, A. T. (2016). The Roles of the High and Low Molecular Weight Isoforms of Fibroblast Growth Factor 2 in Ischemia-Induced Revascularization [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460444581

    APA Style (7th edition)

  • Adeyemo, Adeola. The Roles of the High and Low Molecular Weight Isoforms of Fibroblast Growth Factor 2 in Ischemia-Induced Revascularization. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460444581.

    MLA Style (8th edition)

  • Adeyemo, Adeola. "The Roles of the High and Low Molecular Weight Isoforms of Fibroblast Growth Factor 2 in Ischemia-Induced Revascularization." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460444581

    Chicago Manual of Style (17th edition)