Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems.
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.
Department of Biological and Environmental Science and Technologies, University of Salento, Lecce, Italy.
Emanuela
E
Urso
Michele
M
Maffia
D000251:Adenosine Triphosphatases / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D027682:Cation Transport Proteins / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000097:blood / Q000378:metabolism*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D006801:Humans; D056511:Metallochaperones / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011328:Prions / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D027682:Cation Transport Proteins; D002614:Chelating Agents; D000079923:Copper Transporter 1; D056511:Metallochaperones; D011328:Prions; C490079:SLC31A1 protein, human; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases