Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

Abstract

Angiogenesis critically sustains the progression of both physiological and pathological processes. Copper behaves as an obligatory co-factor throughout the angiogenic signalling cascades, so much so that a deficiency causes neovascularization to abate. Moreover, the progress of several angiogenic pathologies (e.g. diabetes, cardiac hypertrophy and ischaemia) can be tracked by measuring serum copper levels, which are being increasingly investigated as a useful prognostic marker. Accordingly, the therapeutic modulation of body copper has been proven effective in rescuing the pathological angiogenic dysfunctions underlying several disease states. Vascular copper transport systems profoundly influence the activation and execution of angiogenesis, acting as multi-functional regulators of apparently discrete pro-angiogenic pathways. This review concerns the complex relationship among copper-dependent angiogenic factors, copper transporters and common pathological conditions, with an unusual accent on the multi-faceted involvement of the proteins handling vascular copper. Functions regulated by the major copper transport proteins (CTR1 importer, ATP7A efflux pump and metallo-chaperones) include the modulation of endothelial migration and vascular superoxide, known to activate angiogenesis within a narrow concentration range. The potential contribution of prion protein, a controversial regulator of copper homeostasis, is discussed, even though its angiogenic involvement seems to be mainly associated with the modulation of endothelial motility and permeability.

Advances in the mechanism of high copper diets in restraining pigs growth

“…Copper is a metallic inorganic cation which has redox properties and plays an important role in maintaining the elasticity and integrity of the vessel walls (Urso & Maffia, 2015). In the circulation system of pigs, copper is mostly in the form of ceruloplasmin (CP), which binds to receptors on the surface of the plasma membrane and protects unsaturated fatty acids that are easily oxidized by hydroxyl groups (Colombini, Carratelli, & Alberti, 2016;Hellman & Gitlin, 2002).…”

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

“…Changes in cellular redox state in turn can influence membrane excitability, such as through modulating K + currents. Cu has been shown to interact with extracellular and intracellular signal transduction mechanisms, including modulating NMDA, MAPK, and TrkB signaling, a variety of ion channels, and extracellular matrix/proteases (e.g., collagen lyase, PAI‐1), all of which again can alter membrane excitability (Bucci et al., , ; D'Ambrosi & Rossi, ; Fujie et al., ; Migocka, ; Scheiber et al., ; Urso & Maffia, ; Zlatic et al., ). Our data are consistent with this, showing Cu/Cu depletion‐induced effects involving NMDA, MAPK, TrkB, and NO.…”

Bioactive glass and glass‐ceramic orbital implants

“…Besides exerting an antibacterial effect, copper ions are known to regulate the expression of many factors involved in angiogenesis, such as VEGF, FGF1/2, fibronectin, angiogenin, collagenase, prostaglandin E-1, and ceruloplasmin, which have key roles in initiation (vasodilation and vascular permeabilization), maturation (endothelial cell proliferation, migration, and morphogenesis), and regulation of blood vessel formation. 99,100 From a biomolecular viewpoint, copper-induced angiogenesis is thought to be related with the mitogen-activated protein kinase (MAPK) signaling pathway, leading to endothelial cell sprouting. 101 This property can be helpful to accelerate wound healing, as shown in some animal studies (rat model).…”