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.

Dysregulation of Calpain Proteolytic Systems Underlies Degenerative Vascular Disorders

“…However, it is noteworthy that Capn1 -deficient mice as well as EC-specific Capn2 -deficient mice did not exhibit the lethal vascular defects 23 , 26 ) ; thus, the impact of calpain-dependent angiogenesis on physiological vascular regulations is currently unclear. Please refer to an excellent review for further details of calpain-mediated physiological angiogenesis 86 ) .…”

“…In this regard, growing evidence suggests that the calpain proteolytic systems, comprised of Ca 2+ -dependent intracellular proteases and a calpain endogenous inhibitor, critically contribute to degenerative vascular disorders. Calpains can be potentiated in the presence of pathophysiological stressors, such as inflammatory cytokines, growth factors, bioactive lipids and hypoxic stimulus 10 , 11 ) . As a result, dysregulation of these systems might be responsible for the vascular disorders noted above.…”

Endothelial calpain systems orchestrate myofibroblast differentiation during wound healing

“…Calpains are calcium-dependent intracellular proteases that are activated by exogenous stressors such as physical stress, as well as by cytokines, growth factors, and hypoxia (11)(12)(13). In vascular endothelial cells (ECs), calpain systems are associated with sprouting angiogenesis (14,15). Our previous study showed that calpain proteolyzes suppressor of cytokine signaling 3 (an endogenous inhibitor of Janus kinase/signal transducers and activator of transcription signaling) in angiogenic ECs, sensitizing them to cytokine stimuli (16).…”

Characterization of the Goose <i>CAPN3</i> Gene and its Expression Pattern in Muscle Tissues of Sichuan White Geese at Different Growth Stages

“…CAPN3 is involved in multiple important functions (Zhang et al, 2017) and has drawn great research interest because of its three specific regions (N-terminal, IS1 and IS2) (Ono et al, 2016). For example, defects IS1/2 in CAPN3 lead to limb girdle muscular dystrophy type 2A (LGMD2A) symptoms and other disease (Beckmann and Spencer, 2008).…”

“…Calpains are Ca 2+ -dependent intracellular cysteine proteases that are involved in cell motility (Glading et al, 2002), and apoptosis regulation (Liu et al, 2004), muscle atrophy (Richard et al, 1995), myoblast fusion (Honda et al, 2008), and muscle growth and develop-ment (Sultan et al, 2000;Zhang et al, 2009). To date, 15 isoforms have been identified in humans (Sorimachi and Ono, 2012), and in vertebrates, calpain 1 and calpain 2 have been widely studied among calpain isoforms (Macqueen et al, 2010;Zhang et al, 2017). Among the calpain family members, calpain 3 (CAPN3, previously named p94) is particularly interesting, because in humans, limb-girdle muscular dystrophy type 2A (LGMDA2) is mainly caused by lossof-function mutations of CAPN3 (Richard et al, 1995).…”