Microvascular Lesions by Estrogen-Induced ID3: Its Implications in Cerebral and Cardiorenal Vascular Disease

Abstract

Severe symptoms of cerebral and cardiorenal vascular diseases can be triggered when cerebral, coronary, or glomerular arterioles grow inappropriately as a result of abnormal cell proliferation. The risk factor(s) and molecular mechanisms responsible for microvascular lesion formation are largely unknown. Although controversial, both animal and epidemiological studies have shown that estrogen increases the risk of stroke which may be due to microvascular lesions. Since microvascular diseases are characterized by excessive vessel growth, it is plausible that estrogen-induced neovascularization contributes to the growth of microvascular lesions. We present evidence for how ID3 overexpression in endothelial cells contributes to the development of an estrogen-induced neovascular phenotype with an additional focus on Pyk2 kinase. Our data showed that ID3 overexpression increased neovascularization, cell migration, and spheroid growth of human cerebral microvascular endothelial cells, hCMEC/D3. ID3 overexpressing cells showed significant estrogen-induced G2/M phase transition. Estrogen treatment increased both ID3 phosphorylation and total protein that was inhibited by tamoxifen; and Pyk2 mediated estrogen-induced ID3 mRNA expression. These findings suggest that Pyk2 signals ID3 expression and ID3 is necessary for estrogen-induced neovascularization in hCMEC/D3 cells. A better understanding of how microvascular lesions depend on ID3 may open new avenues for prevention and treatment of neurological diseases.

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.…”

Inhibitor of DNA-Binding/Differentiation Proteins and Environmental Toxicants: Genomic Impact on the Onset of Depressive Dysfunction

“…Higher ID3 protein expression matched with a greater quantity of oxidative DNA injury marker 8-OHdG in blood vessels. Overall, this shows the conceivable function of ID3 in regulating micro-vascular lesion growth and vascular endothelial cell survival driven by environmental toxicants such as PCB153 [37][38]. Another study investigated how exposure to BPA stimulated reproductive anomalies in adult male testis.…”

“…Additionally, it was shown by Das et al that exposure of 17-β estradiol (E2) with estrogenic endocrine disruptors (EEDs) such as polychlorinated biphenyl 153 (PCB153) to vascular endothelial cells (ECs) proliferate ROS [37]. Since ID proteins such as ID3 are redox-sensitive, it acts as an essential factor of the ROS-stimulated proliferation of ECs and E2 to PCB153 [37][38][39]. Depression, which is categorized as a mood disorder is triggered when neurotransmitters, that are chemical messengers that help the brain communicate with parts of the body, are out of equilibrium.…”

Contribution of Inhibitor of Differentiation and Estrogenic Endocrine Disruptors to Neurocognitive Disorders

“…Similarly, in another study Das et al [ 34 ] have shown the exposure of 17-β estradiol (E2) and estrogenic endocrine disruptors (EED) like polychlorinated biphenyl 153 (PCB153) to vascular endothelial cells (ECs) increase ROS. While ID3 is a redox-sensitive gene, it acts as an important determinant of the ROS-induced proliferation of E2 and ECs exposed to PCB153 [ 34 , 35 , 36 ]. Neurodegenerative disorders like Alzheimer’s and Parkinson’s are the main causes of dementia, and their symptoms worsen slowly over the time.…”

“…Elevated ID3 protein expression compared with a larger amount of oxidative DNA damage marker 8-OHdG in blood vessels. The results provide the potential role of ID3 in regulating development of micro-vascular lesions and vascular endothelial cell survival prompted by environmental chemicals such as PCB153 [ 34 , 35 ]. Furthermore, another study determined if in utero exposure to BPA stimulated reproductive tract irregularities in the adult male testis.…”