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Adventitial Fibroblast Nox4 Expression and ROS Signaling in Pulmonary Arterial Hypertension

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Pulmonary Vasculature Redox Signaling in Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 967))

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease arising from remodeling and narrowing of pulmonary arteries (PA) resulting in high pulmonary arterial blood pressure and ultimately right ventricular failure. Elevated production of reactive oxygen species (ROS) by NADPH oxidase 4 (Nox4), a constitutively active enzyme, has been associated with oxygen sensing, vasomotor control, cellular proliferation, differentiation, migration, apoptosis, senescence, fibrosis, and angiogenesis. Further, elevated expression of Nox4 has been reported in a number of cardiovascular diseases, including atherosclerosis, hypertension, cardiac failure, ischemic stroke, and PAH. However, the cellular location of Nox4 and its contribution to aberrant vascular remodeling in PAH remains poorly understood. The goal of this review is to summarize the recent literature on the enzymatic regulation of Nox4 in the production of ROS in PAH. In the vascular wall, Nox4 is present in fibroblasts, a primary cell of the adventitia, and matches the adventitial location of ROS production in PAH. Further, in adventitial fibroblasts, Nox4 overexpression stimulates migration and proliferation as well as matrix gene expression. Collectively, reports indicate that Nox4 contributes to altered fibroblast behavior, ROS production leading to hypertensive vascular remodeling and the development of PAH. Finally, we address the functional significance of Nox4 in fibroblasts, and also suggest an “outside in” (adventitial) process of vascular remodeling that is mediated by Nox4, which although has physiological roles in the intimal layer (i.e., endothelium), may also have pathologic importance in the adventitial layer of the vascular wall through signaling in fibroblasts.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, 30912, USA

    Scott A. Barman Ph.D., FAHA

  2. Vascular Biology Center, Augusta University, Augusta, GA, 30912, USA

    David Fulton Ph.D.

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  1. Scott A. Barman Ph.D., FAHA
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Correspondence to Scott A. Barman Ph.D., FAHA .

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  1. Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, USA

    Yong-Xiao Wang

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Barman, S.A., Fulton, D. (2017). Adventitial Fibroblast Nox4 Expression and ROS Signaling in Pulmonary Arterial Hypertension. In: Wang, YX. (eds) Pulmonary Vasculature Redox Signaling in Health and Disease. Advances in Experimental Medicine and Biology, vol 967. Springer, Cham. https://doi.org/10.1007/978-3-319-63245-2_1

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