Fibroblast Growth Factor signaling in heart injury and repair Summary In response to injury, as in the case of cardiovascular disease (CVD), cells and tissues often reactivate developmental signaling pathways to repair damage or regenerate tissue. This can result in both beneficial and harmful consequences. To manipulate injury response mechanisms in a beneficial way, it is essential to understand the normal developmental pathways and how they are reactivated in adult tissues. In this proposal, we focus on Fibroblast Growth Factors (Fgfs), which are required for embryonic heart development, neonatal myocardial growth and the response to myocardial injury. Developmental and pathological studies demonstrate important interactions between cardiomyocytes, epicardial cells and cells derived from the epicardium, and vascular components of the heart. Recent evidence suggests that FGF signaling pathways regulate all three components of the heart during development and during the response to injury. Loss of FGF signaling in either epicardial or myocardial tissues impairs normal development and results in decreased heart size. Following injury to the heart in both humans and mice, FGF signaling increases, indicating that FGF signaling pathways may be necessary for cardiac repair. Following myocardial infarction, hearts lacking Fgf2 show reduced fibroblast proliferation and collagen deposition, decreased endothelial proliferation and vascular density, decreased cardiomyocyte hypertrophy, increased final infarct size (infarct expansion), and impaired cardiac function. Transgenic mice that overexpress Fgf2 in cardiomyocytes have decreased infarct sizes and increased recovery of function compared to WT hearts. These studies indicate an essential role for endogenous FGF2 in the heart's response to ischemic injury. Here we will explore the molecular, cellular and physiological mechanisms by which FGF signaling regulates interactions between myocardial, epicardial-derived and vascular components of the heart during homeostasis, physiological stress and response to injury (myocardial infarction). We propose to: 1) Identify the cellular targets of FGF2 required for cardioprotection; 2) Test the hypothesis that FGF9 and FGF16 function in vivo in the adult heart to limit FGF activity; 3) Identify molecular mechanisms that regulate cardiomyocyte responsiveness to FGFs in neonatal, adult and injured cardiomyocytes. These studies will provide essential new information about CVDs that are most likely to respond to FGF- based therapy, cell types that would be expected to show a beneficial (or detrimental) response to FGFs, and the mechanisms that regulate FGF activity in the context of potential endogenous inhibitors. This knowledge will be essential to effectively design and implement FGF-based therapies for the treatment of human CVD.

Public Health Relevance

Fibroblast Growth Factor signaling in heart injury and repair Public Health relevance: Cardiovascular disease accounts for 34% of all deaths in the United States. In response to injury, as in the case of cardiovascular disease, cells and tissues often reactivate developmental signaling pathways to repair damage or regenerate tissue. To understand and thus modify injury response mechanisms, it is essential to understand the normal developmental pathways. Fibroblast Growth Factors (FGFs) have been proposed as important regulators of development and function of the cardiovascular system. The research in this proposal will advance our knowledge of FGF signaling pathways in the adult heart and will determine how FGF signaling pathways are used and regulated under normal physiological conditions and during the response of the heart to ischemic injury. These studies will provide essential knowledge about which types of cardiovascular diseases are most likely to respond to FGF-based therapy, how to optimally target FGF activity to the correct cell(s), and how to regulate FGF activity in the context of potential endogenous inhibitory mechanisms. This knowledge will be essential to design and implement effective FGF-based therapies for the treatment of human cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105732-05
Application #
8782498
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
5
Fiscal Year
2015
Total Cost
$342,000
Indirect Cost
$117,000
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
House, Stacey L; Castro, Angela M; Lupu, Traian S et al. (2016) Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 310:H559-71
Xia, Xue; Kumru, Ozan S; Blaber, Sachiko I et al. (2016) Engineering a Cysteine-Free Form of Human Fibroblast Growth Factor-1 for ""Second Generation"" Therapeutic Application. J Pharm Sci 105:1444-53
Park, Changwon; Lee, Tae-Jin; Bhang, Suk Ho et al. (2016) Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2. Arterioscler Thromb Vasc Biol 36:86-96
Ornitz, David M; Itoh, Nobuyuki (2015) The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol 4:215-66
House, Stacey L; Wang, Joy; Castro, Angela M et al. (2015) Fibroblast growth factor 2 is an essential cardioprotective factor in a closed-chest model of cardiac ischemia-reperfusion injury. Physiol Rep 3:
Kim, Ju Young; Lee, Ra Ham; Kim, Tae Min et al. (2014) OVOL2 is a critical regulator of ER71/ETV2 in generating FLK1+, hematopoietic, and endothelial cells from embryonic stem cells. Blood 124:2948-52
Lavine, Kory J; Epelman, Slava; Uchida, Keita et al. (2014) Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc Natl Acad Sci U S A 111:16029-34
Oladipupo, Sunday S; Smith, Craig; Santeford, Andrea et al. (2014) Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. Proc Natl Acad Sci U S A 111:13379-84
Gay, Denise; Kwon, Ohsang; Zhang, Zhikun et al. (2013) Fgf9 from dermal ?? T cells induces hair follicle neogenesis after wounding. Nat Med 19:916-23
Cilvik, Sarah N; Wang, Joy I; Lavine, Kory J et al. (2013) Fibroblast growth factor receptor 1 signaling in adult cardiomyocytes increases contractility and results in a hypertrophic cardiomyopathy. PLoS One 8:e82979

Showing the most recent 10 out of 12 publications