Redox balance dynamically regulates vascular growth and remodeling

Abstract

Vascular growth and remodeling responses entail several complex biochemical, molecular, and cellular responses centered primarily on endothelial cell activation and function. Recent studies reveal that changes in endothelial cell redox status critically influence numerous cellular events that are important for vascular growth under different conditions. It has been known for some time that oxidative stress actively participates in many aspects of angiogenesis and vascular remodeling. Initial studies in this field were largely exploratory with minimal insight into specific molecular mechanisms and how these responses could be regulated. However, it is now clear that intracellular redox mechanisms involving hypoxia, NADPH oxidases (NOX), xanthine oxidase (XO), nitric oxide and its synthases, and intracellular antioxidant defense pathways collectively orchestrate a redox balance system whereby reactive oxygen and nitrogen species integrate cues controlling vascular growth and remodeling. In this review, we discuss key redox regulation pathways that are centrally important for vascular growth in tissue health and disease. Important unresolved questions and issues are also addressed that requires future investigation.

Figure 1. ROS dependent modulation of vascular growth responses for physiological and pathological conditions

The left side of the figure highlights physiological angiogenesis examples that involve low regulated levels of ROS production. The right side of the figure lists pathological angiogenesis situations that involve abundant or prolonged ROS generation contributing to various disease processes.

Figure 2. Major enzymatic and intracellular sources of ROS production

Membrane associated NADPH oxidase (NOX) complex assembly is a major source of O₂^•− production; however, the NOX4 isoform may also constitutively produce H₂O₂. eNOS uncoupling produces O₂^•− due low bioavailability of cofactors NADPH, BH4 and/or L-arginine substrate that can then react with NO to form peroxynitrite. XO produces both superoxide and H₂O₂ with O₂^{• –} production occurring under higher O₂ tension (10-21% O₂) and H₂O₂ generation at lower O₂ tension (1% O₂). O₂^{• −} is also dismutated to H2O2 by Cu and Zn dependent superoxide dismutase (CuZnSOD) within the cytosol. Mitochondria also produce O₂^{• –} and H₂O₂ due to respiratory chain dysfunction (RCD) that regulated by Mn dependent superoxide dismutase (MnSOD).

Figure 3. Prominent angiogenic signaling pathways regulated by ROS

ROS production from all sources; NOX isoforms, uncoupled eNOS, XO and mitochondria directly influence numerous signaling pathways (e.g. PKC, RTK, p38 MAPK, and ERK1/2) involving both inhibition of regulatory phosphatase activity or activation of kinase activity. Subsequent redox dependent signaling stimulates activation of various transcription factors including HIF-1, NF-kB, Ets and others followed by up-regulation of angiogenic molecules such as VEGF, MMP and uPA that stimulate endothelial cell proliferation and migration thus increasing angiogenesis activity.