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Updated: Jul 13, 2026
Assessing Therapeutic Angiogenesis in a Murine Model of Hindlimb Ischemia
Published on: June 8, 2019
Calreticulin downregulation is associated with FGF-2-induced angiogenesis through calcineurin pathway in ischemic
Xiuhua Liu1, Xudong Wu, Lirong Cai
1Department of Pathophysiology, PLA General Hospital, Beijing, China. xiuhualiu98@yahoo.com.cn
Abstract:
Fibroblast growth factor 2 (FGF-2) plays an integral role in therapeutic angiogenesis associated with myocardial infarct healing. Calcium (Ca(2+)) is one of the most universal important signaling molecules that affect cell proliferation and angiogenesis. Calreticulin (CRT), a 46-kd (Ca(2+)) -binding chaperone found mainly in the endoplasmic reticulum, plays an important role in regulating calcium homeostasis. The role of CRT in FGF-2-induced angiogenesis and its signaling pathways in ischemic myocardium are not clear. For this study, two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization mass spectrometry were used to analyze CRT's differential expression in myocardial microvascular endothelial cells treated with or without FGF-2. Western blotting analysis was used to detect the expression of CRT and calcineurin (CaN) in sham-operated, FGF-2-, or saline intramyocardially injected myocardium. It is found that FGF-2 induced angiogenesis after sustained ischemia with downregulation of CRT expression and upregulation of CaN expression in myocardium. The CRT expression was negatively correlated to angiogenesis. Furthermore, overexpression of CRT or inhibition of CaN with cyclosporine A abolishes FGF-2-induced microvascular endothelial cells proliferation and CaN expression. The results indicate that intramyocardial administration of FGF-2 decreases myocardial CRT expression in parallel with myocardial angiogenesis in ischemic myocardium. The study further indicates that Ca(2+)/CaN signaling pathway may be involved in CRT-related angiogenesis.
Insights
Fibroblast growth factor 2 (FGF-2) promotes therapeutic angiogenesis in heart attack healing by downregulating calreticulin (CRT) and upregulating calcineurin (CaN). This suggests Ca(2+)/CaN signaling is involved in CRT-related angiogenesis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cell Signaling
Background:
- Fibroblast growth factor 2 (FGF-2) is crucial for therapeutic angiogenesis in myocardial infarct healing.
- Calcium (Ca(2+)) signaling regulates cell proliferation and angiogenesis.
- Calreticulin (CRT) is a calcium-binding chaperone involved in calcium homeostasis.
Purpose of the Study:
- To investigate the role of CRT in FGF-2-induced angiogenesis and its signaling pathways in ischemic myocardium.
- To elucidate the relationship between CRT expression and angiogenesis in the context of FGF-2 treatment.
Main Methods:
- Differential expression analysis of CRT in myocardial microvascular endothelial cells using 2D gel electrophoresis and MALDI-TOF MS.
- Western blotting to detect CRT and calcineurin (CaN) expression in vivo.
- Functional assays involving CRT overexpression and CaN inhibition with cyclosporine A.
Main Results:
- FGF-2 treatment led to decreased CRT expression and increased CaN expression in ischemic myocardium, correlating negatively with angiogenesis.
- Overexpression of CRT or inhibition of CaN abolished FGF-2-induced endothelial cell proliferation.
- FGF-2 administration resulted in decreased myocardial CRT expression alongside increased myocardial angiogenesis.
Conclusions:
- Intramyocardial FGF-2 administration downregulates myocardial CRT expression during angiogenesis in ischemic conditions.
- The Ca(2+)/CaN signaling pathway is implicated in CRT-mediated angiogenesis.
- CRT may serve as a novel therapeutic target for modulating angiogenesis in ischemic heart disease.
