Direct antiangiogenic actions of cadmium on human vascular endothelial cells

Abstract

The vascular endothelium is a primary target of cadmium (Cd) toxicity, but little is known regarding a potential mechanism whereby Cd may inhibit angiogenesis. Recent findings showing that Cd can disrupt cadherin-mediated cell-cell adhesion suggested that Cd might inhibit angiogenesis by altering the function of VE-cadherin, a molecule that is essential for angiogenesis. To address this issue, endothelial cells (ECs) were exposed to Cd in the presence of serum and subjected to angiogenesisrelated cell migration and tube formation assays. Initial examination of cytotoxicity showed that ECs are rather resistant to the acute cytotoxic effects of Cd even at concentrations up to 1mM. However, 10μM Cd decreased migration of ECs. Cd concentrations of 500nM and greater significantly reduced organization of microvascular ECs into tubes. These antiangiogenic effects were evident even when ECs were preincubated with Cd and then washed to remove free Cd, indicating that Cd acted directly on the cells rather than on the extracellular matrix. Immunolocalization studies showed that Cd caused the redistribution of VE-cadherin from cell-cell contacts. These findings indicate that Cd acts in an angiostatic manner on ECs, and that this effect may involve alterations in the localization and function of VE cadherin.* Abbreviations Cd = cadmium DMSO = dimethylsulfoxide EBM-2 = endothelial basal media-2 EC = endothelial cell EGM-2 = endothelial growth media-2 FBS = fetal bovine serum HMVEC = human dermal microvascular endothelial cell HUVEC = human umbilical vein endothelial cell PMA = phorbol 12-myristate 13-acetate ‡ Corresponding author:

Toxic effects of cadmium on testis of birds and mammals: A review

“…It was found that the initial effect of acute Cd administration is on the integrity of the vascular endothelium (Nolan and Shaikh, 1986). Later, numerous studies reported disruptive effects of Cd on human endothelial cells (Helmestam et al, 2010;Majumder et al, 2008;Woods et al, 2008), which revealed also dysfunctional and antiangiogenic actions of Cd (Kolluru et al, 2006;Woods et al, 2008). First signs of endothelial damage appears early since discontinuities in endothelial lining appeared within 1-2 h following parenteral injection of Cd in dose 3 M/100 g bw (Aoki and Hoffer, 1978).…”

Cadmium and cardiovascular diseases: cell biology, pathophysiology, and epidemiological relevance

“…This effect causes the opening of gaps between endothelial cells as well as the contraction of endothelial cells, which allows for increased permeability of the vascular endothelium (Sacerdote and Cavicchia 1983;Shukla et al 1996;Prozialeck et al 2006). The molecular details are still not clear yet, but the phenomenon is not specific for VEcadherin and endothelial cells, is not associated with a loss of plasma membrane integrity, but seems to affect several members of the cadherin protein family and different cell types (Pearson et al 2003;Woods et al 2008). Since cadherin-cadherin bonds are Ca 2?…”

“…Since cellular proliferation and angiogenesis play an important role in CVDs, the effects of Cd on those phenomena were also addressed in the past, yet to marginal extent. Cd was shown to inhibit both, endothelial proliferation (Messner et al 2009) and angiogenesis (Woods et al 2008). Inhibition of endothelial proliferation and angiogenesis significantly abrogates endothelial wound healing, another phenomenon that contributes to deterioration of endothelial function.…”

“…Cd reduces endothelial barrier function by the disruption of endothelial cell-cell adhesions and by causing endothelial cell death, which has been demonstrated in vivo and in vitro (Sacerdote and Cavicchia 1983;Prozialeck et al 2006;Messner et al 2009). In conjunction with that, Cd-mediated inhibition of endothelial wound healing may cause a permanent shift from a closed towards a more open and permeable endothelium (Woods et al 2008;Messner et al 2009). Based on the ''response to injury hypothesis'', this damage allows for an increased and less controlled permeation and infiltration of the endothelium by cells of the immune system, and facilitates increased permeation and accumulation of lipids in the vessel wall.…”

Cardiac Tissue Injury Resistance During Myocardial Infarction at Adulthood by Developmental Exposure to Cadmium

“…Most studies with cultured cells directly exposed to Cd 2? demonstrated a negative regulation of the production of pro-angiogenic factors or direct anti-angiogenic actions [22,23]. Conversely, there are few studies revealing paradoxical action of Cd 2?…”