Oxidant-dependent regulation of L-type calcium channel activity by angiotensin in vascular smooth muscle

Resistance arteries are a major point of physiological regulation of blood flow. Increases in vessel wall stress or sympathetic activity stimulate vascular wall angiotensin signaling, resulting in smooth muscle contraction which directly increases peripheral resistance. Calcium influx through voltage-gated L-type calcium channels underlies vascular smooth muscle contraction. Roughly half of calcium influx in these cells occurs through a small number of persistently active channels, whose activity increases with membrane depolarization. The number of channels gating in this manner is increased by activation of angiotensin receptors on the cell membrane, and basal L-type channel activity is increased during hypertension. Reactive oxygen species are also generated by vascular smooth muscle in response to vessel stretch and by several paracrine signaling pathways including angiotensin signaling. Oxidative stress and augmented calcium handling resulting from chronic angiotensin signaling in the vasculature each contribute to enhanced vessel reactivity, pathological inflammation and vessel remodeling associated with hypertension. This study uses a multidisciplinary approach to investigate the role of hydrogen peroxide in angiotensin signaling in vascular smooth muscle. Using calcium- and redox-sensitive fluorescent indicators, local generation of hydrogen peroxide by NAD(P)H oxidase and mitochondria are shown to synergistically promote PKC-dependent persistent gating of plasma membrane L- type calcium channels in response to angiotensin II. We show that broad inhibition of hydrogen peroxide signaling by catalase and targeted inhibition of mitochondrial reactive oxygen species production attenuates cerebral resistance artery constriction to angiotensin. We further demonstrate the role of endothelium-independent mitochondrial reactive oxygen species in development of enhanced vessel tone and smooth muscle calcium in a murine model of hypertension. Together, these findings contribute to the understanding of intracellular calcium and oxidative signaling in vascular physiology and disease and may provide insight into local signaling dynamics involving these second messengers in various other systems.

Name thesis:degree_name

Doctor of Philosophy (Ph.D.)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biomedical Sciences

Grantor dc:publisher

Colorado State University. Libraries

Year dc:date.issued

2015

Authors dc:creator

• Chaplin, Nathan L., author
• Amberg, Gregory, advisor
• DeLuca, Jennifer, committee member
• Tamkun, Michael, committee member
• Tsunoda, Susan, committee member

• angiotensin
• L-type calcium channel
• mitochondria
• NAD(P)H oxidase
• reactive oxygen species
• vascular smooth muscle

Statement dc:rights

• Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.

Language dc:language.iso

eng, English

Identifier URI

https://doi.org/10.25675/3.018612

OAI identifier oai:identifier

oai:mountainscholar.org:10217/170373