Synovial neovascularization plays a critical role in the pathogenesis of rheumatoid arthritis (RA) and is required for inflammatory cell infiltration, expansion of synovial cells and pannus formation. Understanding the mechanisms that control neovascular process is important because it will identify key molecules as targets for pharmacologic blockade by specific inhibitors and receptor antagonists. Recently, it has been noted that endothelial progenitor cells (EPCs) are recruited to inflamed synovium and participate in synovial neovascularization in arthritis. The mechanism for EPC homing, however, remainsunknown and the following important issues need to be addressed: How are EPCs regulated under the inflammatory conditions in arthritis ? What are the cellular and molecular mechanisms for EPC homing to inflamed synovium ? How do EPCs differentiate into new blood vessels and to what extent do they contribute to synovial neovascularization ? Clinical and experimental arthritis is associated with in vivo activation of the plasma kallikrein-kinin system (KKS). Bradykinin, the activation product of the KKS, mediates inflammatory response in arthritis through its receptors B1R and B2R. The applicant has recently found that EPCs express B2R, and bradykinin stimulates transendothelial migration of EPCs. In this R03 proposal, the central hypothesis is that activation of the KKS, via the release of bradykinin, stimulates synovial recruitment of EPCs in arthritis. This hypothesis is innovative because in the synovial neovascularization, the role of the KKS, which is a primary mediator of inflammation, is unclear. In the proposed studies, animal models, cell biological, pharmacological, biochemical and molecular approaches will be used. The hypothesis will be tested through the pursuit of the following two specific aims:
Specific Aim 1 will determine whether activation of the KKS stimulates EPC homing to inflamed synovium and participation in synovial neovascularization in arthritis. The applicant has succeeded in isolating EPCs from Lewis rats and detecting synovial recruitment of implanted EPCs. Association of the KKS activation with EPCs-mediated new vessel formation will be examined by using plasma kallikrein inhibitor, anti-kininogen antibody and kininogen deficient animal model.
Specific Aim 2 will define the role of bradykinin receptors, B1R and B2R, in synovial recruitment of EPCs. The effect of bradykinin on synovial recruitment of EPCs will be evaluated in a rat model of knee joint perfusion. The applicant will also test whether upregulation of kinin receptors potentiates bradykinin-stimulated homing of EPCs. The role of each kinin receptor in synovial recruitment of EPCs will be determined by using specific antagonists or gene silencing of kinin receptors. These proposed investigations will not only initiate further studies of the cellular and molecular mechanisms for EPC homing and differentiation in arthritis, but will also improve in depth understanding of the pathophysiological role of the KKS in synovial neovascularization.

Public Health Relevance

Project Narrative Synovial neovascularization is critical for the pathogenesis of rheumatoid arthritis. The proposed research examines the regulation of endothelial progenitor cells (EPCs) by plasma kallikrein-kinin system and determines the contribution of EPCs to synovial neovascularization. This project will provide novel insight into the mechanism of synovial neovascularization and will identify potential therapeutic targets for treatment of arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR057542-03
Application #
8088038
Study Section
Special Emphasis Panel (ZAR1-MLB-G (M1))
Program Officer
Mao, Su-Yau
Project Start
2009-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$71,280
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Yang, Aizhen; Zhou, Junsong; Wang, Bo et al. (2017) A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis. FASEB J 31:5419-5431
Yang, Aizhen; Xie, Zhanli; Wang, Bo et al. (2017) An essential role of high-molecular-weight kininogen in endotoxemia. J Exp Med :
Yang, Aizhen; Dai, Jihong; Xie, Zhanli et al. (2014) High molecular weight kininogen binds phosphatidylserine and opsonizes urokinase plasminogen activator receptor-mediated efferocytosis. J Immunol 192:4398-408
Zhu, Xuemei; Zheng, Xichen; Wu, Yi (2014) Cleaved high molecular weight kininogen stimulates JNK/FOXO4/MnSOD pathway for induction of endothelial progenitor cell senescence. Biochem Biophys Res Commun 450:1261-5
Xie, Zhanli; Dai, Jihong; Yang, Aizhen et al. (2014) A role for bradykinin in the development of anti-collagen antibody-induced arthritis. Rheumatology (Oxford) 53:1301-6
Dai, Jihong; Agelan, Alexis; Yang, Aizhen et al. (2012) Role of plasma kallikrein-kinin system activation in synovial recruitment of endothelial progenitor cells in experimental arthritis. Arthritis Rheum 64:3574-82
Dai, Jihong; Zhu, Xuemei; Yoder, Mervin C et al. (2011) Cleaved high-molecular-weight kininogen accelerates the onset of endothelial progenitor cell senescence by induction of reactive oxygen species. Arterioscler Thromb Vasc Biol 31:883-9
Wu, Y; Dai, J; Schmuckler, N G et al. (2010) Cleaved high molecular weight kininogen inhibits tube formation of endothelial progenitor cells via suppression of matrix metalloproteinase 2. J Thromb Haemost 8:185-93