The goal of this dissertation was to test the hypothesis that fibroblast growth factor-2 (FGF2) is required during diseased-related vascular growth and remodeling in the adult organism. Given previous research, it is generally assumed that FGF2 is an important regulator of vessel growth during various pathophysiological processes (e.g. tissue ischemia, vessel injury, and flow-dependent remodeling). However, such studies only indirectly implicate FGF2 in vascular adaptation and remodeling. In contrast, experiments using mice with a targeted disruption of the Fgf2 gene have allowed direct determination of the biological roles of endogenous FGF2. Thus, experimental models of flow-dependent remodeling and ischemic revascularization were used to compare the responses of Fgf2⁻/⁻ and Fgf2⁺/⁺ mice to directly identify the function of FGF2 during vascular adaptation in the adult animal. Surprisingly, the lack of FGF2 did not appear to affect vascular growth in these models. First, using a novel model of flow-dependent remodeling, Fgf2⁻/⁻ mice had equivalent carotid artery adaptation in response to both high-flow and low-flow was as wildtype counterparts. Second, angiogenesis and arteriogenesis were not different between the ischemic limbs Fgf2⁺/⁺ and Fgf2⁻/⁻ mice, demonstrating that FGF2 is not required for vascular adaptation in response to ischemia. However, these experiments led to the observation that reactive hyperemia was impaired in ischemic limb of Fgf2⁻/⁻ mice. These results indicate that vessel responsiveness is altered in the collateral circulation of the ischemic Fgf2⁻/⁻ limb. This possible identification of FGF2 as a "functional" factor in the collateral circulation suggests a novel, non-mitogenic role for endogenous growth factors. Finally, Fgf2⁻/⁻ mice had altered gene expression in the ischemic limb as evaluated using cDNA microarrays. The significance of differential gene expression in the absence of FGF2 is unknown. It is unclear whether such changes in gene expression are related to the FGF2 hyperemia phenotype or whether they are related to an unknown phenotype present in the ischemic limb of Fgf2⁻/⁻ mice. Overall, this dissertation provides new evidence that endogenous FGF2 has important actions in the remodeling vasculature during ischemic revascularization. Specifically, endogenous FGF2 appears to modulate vascular reactivity of the collateral circulation of the hindlimb.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/284317 |
| Date | January 2002 |
| Creators | Sullivan, Christopher James |
| Contributors | Hoying, James B. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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