title: Endothelial cell calpain as a critical modulator of angiogenesis.
abstract: Calpains are a family of calcium-dependent non-lysosomal cysteine proteases. In particular, calpains residing in the endothelial cells play important roles in angiogenesis. It has been shown that calpain activity can be increased in endothelial cells by growth factors, primarily vascular endothelial growth factor (VEGF). VEGF/VEGFR2 induces calpain 2 dependent activation of PI3K/AMPK/Akt/eNOS pathway, and consequent nitric oxide production and physiological angiogenesis. Under pathological conditions such as tumor angiogenesis, endothelial calpains can be activated by hypoxia. This review focuses on the molecular regulatory mechanisms of calpain activation, and the newly identified mechanistic roles and downstream signaling events of calpains in physiological angiogenesis, and in the conditions of pathological tumor angiogenesis and diabetic wound healing, as well as retinopathy and atherosclerosis that are also associated with an increase in calpain activity. Further discussed include the differential strategies of modulating angiogenesis through manipulating calpain expression/activity in different pathological settings. Targeted limitation of angiogenesis in cancer and targeted promotion of angiogenesis in diabetic wound healing via modulations of calpains and calpain-dependent signaling mechanisms are of significant translational potential. Emerging strategies of tissue-specific targeting, environment-dependent targeting, and genome-targeted editing may turn out to be effective regimens for targeted manipulation of angiogenesis through calpain pathways, for differential treatments including both attenuation of tumor angiogenesis and potentiation of diabetic angiogenesis.
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA; Division of Cardiology, Department Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA; Division of Cardiology, Department Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA.
authors.forename: Norika Mengchia
authors.initials: NM
authors.lastname: Liu
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA; Division of Cardiology, Department Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA.
authors.forename: Yongchen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA; Division of Cardiology, Department Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA.
authors.forename: Ji Youn
authors.initials: JY
authors.lastname: Youn
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA; Division of Cardiology, Department Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles (UCLA), CA 90095, USA. Electronic address: hcai@mednet.ucla.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology
chemical_list: D002154:Calpain
keywords: Angiogenesis; Atherosclerosis; Calpain; Diabetic wound healing; Endothelial cells; Retinopathy; Shear stress; Tumor angiogenesis; VEGF; eNOS