Oxidant-Dependent and Oxidant-Independent Proangiogenic and Vasomotor Signaling in Coronary Vascular Endothelium

  • Sarah Aldosari
  • Maan Awad
  • May Z. Gao
  • Isabella G. McCormack
  • Frank W. Sellke
  • Md. Ruhul AbidEmail author


Depending on their levels, source of generation, and subcellular locations, reactive oxygen species (ROS) are known to have paradoxical effects on coronary vascular endothelium. At low concentrations, ROS contribute to physiological signaling pathways that regulate vascular endothelial cell (EC) growth and survival. At higher concentrations, or with prolonged exposure, ROS can exacerbate endothelial cell injury and trigger apoptosis. In this chapter, oxidant-dependent and oxidant-independent angiogenic and vasomotor signaling pathways will be discussed in-depth, including the structures of oxidant-producing enzymes, their agonists, and their related signaling pathways in EC. Vascular endothelial growth factor (VEGF), a major growth factor involved in the maintenance of EC health, vasomotor tone, and angiogenesis, will also be discussed. VEGF utilizes both reactive oxygen species (ROS)-dependent and ROS-independent arms of EC signaling.

In this chapter, NADPH oxidase (NOX)-induced oxidant-dependent angiogenesis will be discussed in-depth, including the structures of all NADPH oxidase isoforms, agonists, and transcription factors that are involved in proangiogenic signaling pathways. We will also discuss vascular endothelial growth factor (VEGF) signaling pathways that are affected by the upregulation of ROS generation.

Previously, increased levels of ROS were believed to be purely associated with pathological conditions as seen in cardiovascular diseases (CVD). Indeed, ROS are produced in higher levels at sites of inflammation and injury by the mitochondria and enzymes, such as NADPH oxidases. Recent findings, as to be discussed in this chapter, have contradicted this notion that ROS are purely a part of pathophysiological pathways. Studies have shown that experimentally reducing global ROS levels does not improve vascular function and recovery as expected. Reducing ROS levels instead results in inhibition of endothelial nitric oxide synthase (eNOS) activation and decreased nitric oxide (NO) synthesis in endothelial cells. Rather than improving vascular function, a global decrease in ROS hinders endothelial function, reduces coronary vasodilation, and inhibits angiogenic signaling. Several recent reports suggest that homeostatic and even above physiological levels of subcellular ROS may contribute to optimal endothelial cell and vascular functions. These studies suggested that the beneficial versus detrimental effects of higher levels of ROS are time-, location- and concentration-dependent.

This chapter will shed light on the overwhelming interconnectedness of NOX, growth factors, and vasoactive factors as well as larger-scale oxidant-dependent and oxidant-independent pathways to elucidate the complexity of signaling in coronary vascular endothelium.


Oxidative stress Reactive oxygen species Vascular endothelium Cardiovascular diseases NADPH oxidase Angiogenesis factor Endothelial nitric oxide synthase Endothelium-dependent relaxing factors Vascular endothelium-dependent relaxation VEGF 



This work was supported in part by the National Heart, Lung, and Blood Institute (NHLBI) and National Institute of General Medical Sciences (NIGMS) grant R01HL133624-01A1 (MRA), HL46716 and R01 128831 (FWS), and American Heart Association Grant-in-Aid 14GRNT20460291 (MRA).


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Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Sarah Aldosari
    • 1
  • Maan Awad
    • 1
  • May Z. Gao
    • 1
  • Isabella G. McCormack
    • 1
  • Frank W. Sellke
    • 1
  • Md. Ruhul Abid
    • 1
    Email author
  1. 1.Cardiovascular Research Center, Cardiothoracic Surgery Division, Rhode Island HospitalBrown University Warren Alpert Medical SchoolProvidenceUSA

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