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Reactive oxygen species (ROS) are natural byproducts of oxygen metabolism in the cell. At physiological levels, they play a vital role in cell signaling. However, high ROS levels cause oxidative stress, which is implicated in cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and restenosis after angioplasty. Despite the great amount of research conducted to identify the role of ROS in CVD, the image is still far from being complete. A common event in CVD pathophysiology is the switch of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. Interestingly, oxidative stress is a major contributor to this phenotypic switch. In this review, we focus on the effect of ROS on the hallmarks of VSMC phenotypic switch, particularly proliferation and migration. In addition, we speculate on the underlying molecular mechanisms of these cellular events. Along these lines, the impact of ROS on the expression of contractile markers of VSMCs is discussed in depth. We conclude by commenting on the efficiency of antioxidants as CVD therapies.

Cutaneous cold-induced vasoconstriction is a normal physiological reaction mediated by alpha 2C-adrenergic receptors (α 2C -ARs) expressed in vascular smooth muscle cells (VSMCs). When this reaction is exaggerated, Raynaud's phenomenon (RP) ensues. RP is more prevalent in females compared to age-matched men. We previously established that 17-β estradiol (estrogen) upregulates α 2C -ARs in human VSMCs via a cAMP/Epac/Rap pathway. We also showed that cAMP acts through JNK to increase α 2C -AR expression. However, whether estrogen employs JNK to regulate α 2C -AR is not investigated. Knowing that the α 2C -AR promoter harbors an activator protein-1 (AP-1) binding site that can be potentially activated by JNK, we hypothesized that estrogen regulates α 2C- AR expression through an Epac/JNK/AP-1 pathway. Our results show that estrogen (10 -10  M) activated JNK in human VSMCs extracted from cutaneous arterioles. Pretreatment with ESI09 (10 μM; an Epac inhibitor), abolished estrogen-induced JNK activation. In addition, pre-treatment with SP600125 (3 μM; a JNK specific inhibitor) abolished estrogen-induced expression of α 2C -AR. Importantly, estrogen-induced activation of α 2C -AR promoter was attenuated with SP600125. Moreover, transient transfection of VSMCs with an Epac dominant negative mutant (Epac-DN) abolished estrogen-induced activation of α 2C -AR promoter. However, co-transfection of constitutively active JNK mutant overrode the inhibitory effect of Epac-DN on α 2C -AR promoter. Moreover, estrogen caused a concentration-dependent increase in the activity of AP-1-driven reporter construct. Mutation of AP-1 site in the α 2C -AR promoter abolished its activation by estrogen. This in vitro estrogen-increased α 2C -AR expression was mirrored by an increase in the ex vivo functional responsiveness of arterioles. Indeed, estrogen potentiated α 2C -AR-mediated cold-induced vasoconstriction, which was abolished by SP600125. Collectively, these results indicate that estrogen upregulates α 2C -AR expression via an EPAC-mediated JNK/AP-1- dependent mechanism. These results provide an insight into the mechanism by which exaggerated cold-induced vasoconstriction occurs in estrogen-replete females and identify Epac and JNK as potential targets for the treatment of RP., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

Cardiovascular disease (CVD) is the major cause of morbidity and mortality worldwide. The implication of estrogen in this disease has been extensively studied. While the vast majority of published research argue for a cardioprotective role of estrogen in vascular inflammation such as in atherosclerosis, the role of estrogen in hypertension remains far from being resolved. The vasorelaxant effect of estrogen has already been well-established. However, emerging evidence supports a vasoconstrictive potential of this hormone. It has been proposed that the microenvironment dictates the effect of estrogen-induced type 1 nitric oxide synthase-1 (nNOS) on vasotone. Indeed, depending on nNOS product, nitric oxide or superoxide, estrogen can induce vasodilation or vasoconstriction, respectively. In this review, we discuss the evidence supporting the vasorelaxant effects of estrogen, and the molecular players involved. Furthermore, we shed light on recent reports revealing a vasoconstrictive role of estrogen, and speculate on the underlying signaling pathways. In addition, we identify certain factors that can account for the discrepant estrogenic effects. This review emphasizes a yin-yang role of estrogen in regulating blood pressure., (Copyright © 2019. Published by Elsevier Inc.)

Remodeling of arterioles is a pivotal event in the manifestation of many inflammation-based cardio-vasculopathologies, such as hypertension. During these remodeling events, vascular smooth muscle cells (VSMCs) switch from a contractile to a synthetic phenotype. The latter is characterized by increased proliferation, migration, and invasion. Compounds with anti-inflammatory actions have been successful in attenuating this phenotypic switch. While the vast majority of studies investigating phenotypic modulation were undertaken in VSMCs isolated from large vessels, little is known about the effect of such compounds on phenotypic switch in VSMCs of microvessels (microVSMCs). We have recently characterized a novel homoisoflavonoid that we called 7- O -methylpunctatin (MP). In this study, we show that MP decreased FBS-induced cell proliferation, migration, invasion, and adhesion. MP also attenuated adhesion of THP-1 monocytes to microVSMCs, abolished FBS-induced expression of MMP-2, MMP-9, and NF-κB, as well as reduced activation of ERK1/2 and FAK. Furthermore, MP-treated VSMCs showed an increase in early (myocardin, SM-22α, SM-α) and mid-term (calponin and caldesmon) differentiation markers and a decrease in osteopontin, a protein highly expressed in synthetic VSMCs. MP also reduced transcription of cyclin D1, CDK4 but increased protein levels of p21 and p27. Taken together, these results corroborate an anti-inflammatory action of MP on human microVSMCs. Therefore, by inhibiting the synthetic phenotype of microVSMCs, MP may be a promising modulator for inflammation-induced arteriolar pathophysiology., Competing Interests: The authors declare no conflict of interest.

Cardiovascular disease (CVD) continues to be the leading cause of death worldwide. The effect of estrogen on these diseases has been assessed in in vitro and in vivo models, as well as in observational studies. Collectively, these studies alluded to a cardiovasculo-protective effect of estrogen. However, comprehensive clinical investigation failed to produce concrete proof of a cardiovascular protective effect for hormone replacement therapy (HRT), let alone rule out potential harm. These seemingly paradoxical effects of estrogen were explained by the 'theory of timing and opportunity'. This theory states that the effect of estrogen, whether cardiovasculo-protective or pathological, significantly depends on the age of the individual when estrogen administration takes place. Here, we review the conflicting effects of estrogen on vascular smooth muscle cells, mainly proliferation and migration as two cellular capacities intimately related to physiology and pathophysiology of the cardiovascular system. Furthermore, we critically discuss the major parameters and signaling pathways that may account for the aforementioned paradoxical observations, as well as the key molecular players involved., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cardiovascular disease (CVD) continues to be the leading cause of death worldwide. Atherosclerosis is a CVD characterized by plaque formation resulting from inflammation-induced insults to endothelial cells, monocytes, and vascular smooth muscle cells (VSMCs). Despite significant advances, current treatments for atherosclerosis remain insufficient, prompting the search for alternative modalities, including herbal medicine. Ziziphus nummularia is an herb commonly used in the amelioration of symptoms associated with many health conditions such as cold, diarrhea, cancer, and diabetes. However, its effect on the inflammation-induced behavior of VSMCs remains unknown. In this study, we sought to determine the effect of the ethanolic extract of Z. nummularia (ZNE) on TNF- α -induced phenotypic changes of human aortic smooth muscle cells (HASMCs). The treatment of HASMCs with ZNE decreased cell proliferation, adhesion to fibronectin, migration, and invasion. ZNE treatment also caused a concentration- and time-dependent reduction in the TNF- α -induced expression of matrix metalloproteases MMP-2 and MMP-9, NF- κ B, and cell adhesion molecules ICAM-1 and VCAM-1. Furthermore, ZNE decreased the adhesion of THP-1 monocytes to HASMCs and endothelial cells in a concentration-dependent manner. These data provide evidence for the anti-inflammatory effect of Ziziphus nummularia , along with potential implications for its use as an agent that could ameliorate inflammation-induced atherogenic phenotype of VSMCs in atherosclerosis.