PCB153-Induced Overexpression of ID3 Contributes to the Development of Microvascular Lesions

Abstract

Microvascular lesions resulting from endothelial cell dysfunction are produced in the brain, lung, kidney, and retina of patients of complex chronic diseases. The environmental and molecular risk factors which may contribute in the development of microvascular damage are unclear. The mechanism(s) responsible for initiating microvascular damage remain poorly defined, although several inciting factors have been proposed, including environmental toxicants-induced oxidative stress. Enhanced neovascularization has been implicated in either the development or progression of proliferative vascular lesions. Here, we present evidence for how PCB-induced ROS may contribute to the development of a neovascular phenotype with the aim of elucidating the role of environmental toxicants in endothelial dysfunction with a specific focus on the inhibitor of differentiation protein ID3. We used a combination of phenotype and immunohistochemical analysis followed by validating with protein expression and post-translational modifications with Western Blot and MALDI-TOF/TOF analysis. We also looked for a correlation between ID3 expression in vascular tissue. Our results showed that PCB-induced ROS mediated a highly tube branched neovascular phenotype that also depended on ID3 and Pyk2; and PCB153 treatment increased the size of endothelial spheroids under conditions typically used for clonal selection of stem cell spheroids. High ID3 protein expression correlated with a greater degree of malignancy and oxidative DNA damage marker 8-OHdG in blood vessels from human subjects. PCB153 treatment increased both serine and tyrosine phosphorylation of endothelial ID3. Stable ID3 overexpression increased cell survival of human microvascular endothelial cell line hCMEC/D3. In summary, our data provide evidence that ID3 may play a critical role in regulating vascular endothelial cell survival and development of microvascular lesions induced by persistent environmental pollutants such as PCB153. Findings of this study are important because they provide a new paradigm by which PCBs may contribute to the growth of microvascular lesions.

Contribution of Inhibitor of DNA Binding/Differentiation-3 and Endocrine Disrupting Chemicals to Pathophysiological Aspects of Chronic Disease

“…We reported that both E2 and PCB153 induced ID3 phosphorylation. E2 treatment stabilized ID3 protein during the 1–6 h treatment time points and increased phosphorylated ID3 levels [10, 21]. It was noteworthy that we showed data of ID3 tyrosine phosphorylation by PCB153 treatment which was confirmed by MALDI-TOF MS/MS spectra data.…”

Possible role of endostatin in the antiangiogenic therapy of diabetic retinopathy

“…Similarly, Id-3 (inhibitor of differentiation protein 3) has been proven to be equally responsible in inducing the endothelial dysfunction due to its significance in reactive-oxygen species (ROS)-induced cellular proliferation of the endothelial cells. Recent studies have concluded the active involvement of Id3 in the development of microvascular lesions in various organs (including the retina of the eye) in people suffering from complex chronic disorders [7]. In case of diabetic retinopathy, the newly generating blood vessels (due to the process of neovascularization) get highly affected by the overexpression of Id-1 and Id-3, which are well known to be responsible for poor vascularization.…”

“…In family of Id proteins, the helix-loop-helix motif is the site of interaction which results in the dimerisation of Id proteins with the basic helix-loop-helix transcription factors. These events result in the negative regulation of the transcription process and are also responsible for the process of neovascularization [7].…”

Pathophysiological Aspects of Vascular Remodeling in Cardiopulmonary Lesions: Influence of ID3 & Estrogenic Endocrine Disruptors

“…Since many of these vascular remodeling mechanisms are oxidative stress dependent [4] [8][9][10]. Based on recent findings that demonstrated ID3 dependent endothelial cell activation via estrogenic PCB153 exposure, we will discuss how exposure to estrogenic endocrine disruptors (EEDs) may contribute to complex vascular lesions, in which cardiopulmonary disease manifest from via ID3 [11]. Previously, we elucidated association between ID3 & EEDs in metabolic syndrome (MetS) perturbations via adipose tissue that bioaccumulate, which can modify various chronic diseases such as vascular, neurological, cancer, and autoimmune [12][13].…”