Voltage-Dependent Anion Channel-2 Interaction with Nitric Oxide Synthase Enhances Pulmonary Artery Endothelial Cell Nitric Oxide Production

In the microcirculation, longitudinal conduction of vasomotor responses provides an essential means of coordinating flow distribution among vessels in a complex network. Spread of current along the vessel axis can display a regenerative component, which leads to propagation of vasomotor signals over many millimeters; the ionic basis for the regenerative response is unknown. We examined the responses to 10 s of focal electrical stimulation (30 Hz, 2 ms, 30 V) of mouse cremaster arterioles to test the hypothesis that voltage-dependent Na+ (Nav) and Ca2+ channels might be activated in long-distance signaling in microvessels. Electrical stimulation evoked a vasoconstriction at the site of stimulation and a spreading, nondecremental conducted dilation. Endothelial damage (air bubble) blocked conduction of the vasodilation, indicating an involvement of the endothelium. The Nav channel blocker bupivacaine also blocked conduction, and TTX attenuated it. The Nav channel activator veratridine induced an endothelium-dependent dilation. The Nav channel isoforms Nav1.2, Nav1.6, and Nav1.9 were detected in the endothelial cells of cremaster arterioles by immunocytochemistry. These findings are consistent with the involvement of Nav channels in the conducted response. BAPTA buffering of endothelial cell Ca2+ delayed and reduced the conducted dilation, which was almost eliminated by Ni2+, amiloride, or deletion of α1H T-type Ca2+ (Cav3.2) channels. Blockade of endothelial nitric oxide synthase or Ca2+-activated K+ channels also inhibited the conducted vasodilation. Our findings indicate that an electrically induced signal can propagate along the vessel axis via the endothelium and can induce sequential activation of Nav and Cav3.2 channels. The resultant Ca2+ influx activates endothelial nitric oxide synthase and Ca2+-activated K+ channels, triggering vasodilation.

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Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression.

Circulation Research ◽

10.1161/01.res.74.2.349 ◽

1994 ◽

Vol 74 (2) ◽

pp. 349-353 ◽

Cited By ~ 569

Author(s):

W C Sessa ◽

K Pritchard ◽

N Seyedi ◽

J Wang ◽

T H Hintze

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Endothelial Cell ◽

Nitric Oxide Synthase ◽

Nitric Oxide Production ◽

Chronic Exercise ◽

Oxide Production ◽

Oxide Synthase

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Non‐Nutritive Sweeteners Reduce Endothelial Cell Nitric Oxide Synthase Activity and Nitric Oxide Production

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.04107 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

L. Madden Brewster ◽

Vinicius Garcia ◽

Hannah Fandl ◽

Kelly Stockelman ◽

Clay Rahaman ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cell ◽

Nitric Oxide Synthase ◽

Nitric Oxide Production ◽

Oxide Production ◽

Oxide Synthase ◽

Nitric Oxide Synthase Activity

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Angiotensin II stimulates nitric oxide production in pulmonary artery endothelium via the type 2 receptor

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00312.2003 ◽

2004 ◽

Vol 287 (3) ◽

pp. L559-L568 ◽

Cited By ~ 23

Author(s):

Susan Olson ◽

Richard Oeckler ◽

Xinmei Li ◽

Litong Du ◽

Frank Traganos ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Angiotensin Ii ◽

Nitric Oxide Synthase ◽

Pulmonary Artery ◽

Nitric Oxide Production ◽

Oxide Production ◽

Oxide Synthase

We previously reported that angiotensin II stimulates an increase in nitric oxide production in pulmonary artery endothelial cells. The aims of this study were to determine which receptor subtype mediates the angiotensin II-dependent increase in nitric oxide production and to investigate the roles of the angiotensin type 1 and type 2 receptors in modulating angiotensin II-dependent vasoconstriction in pulmonary arteries. Pulmonary artery endothelial cells express both angiotensin II type 1 and type 2 receptors as assessed by RT-PCR, Western blot analysis, and flow cytometry. Treatment of the endothelial cells with PD-123319, a type 2 receptor antagonist, prevented the angiotensin II-dependent increase in nitric oxide synthase mRNA, protein levels, and nitric oxide production. In contrast, the type 1 receptor antagonist losartan enhanced nitric oxide synthase mRNA levels, protein expression, and nitric oxide production. Pretreatment of the endothelial cells with either PD-123319 or an anti-angiotensin II antibody prevented this losartan enhancement of nitric oxide production. Angiotensin II-dependent enhanced hypoxic contractions in pulmonary arteries were blocked by the type 1 receptor antagonist candesartan; however, PD-123319 enhanced hypoxic contractions in angiotensin II-treated endothelium-intact vessels. These data demonstrate that angiotensin II stimulates an increase in nitric oxide synthase mRNA, protein expression, and nitric oxide production via the type 2 receptor, whereas signaling via the type 1 receptor negatively regulates nitric oxide production in the pulmonary endothelium. This endothelial, type 2 receptor-dependent increase in nitric oxide may serve to counterbalance the angiotensin II-dependent vasoconstriction in smooth muscle cells, ultimately regulating pulmonary vascular tone.

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Multiple Ca2+-dependent modulators mediate alkalosis-induced vasodilation in newborn piglet lungs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.3.l519 ◽

2001 ◽

Vol 280 (3) ◽

pp. L519-L526 ◽

Cited By ~ 9

Author(s):

Michele A. Vander Heyden ◽

Ted R. Halla ◽

Jane A. Madden ◽

John B. Gordon

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Pulmonary Artery ◽

Newborn Piglet ◽

Channel Activation ◽

Future Studies ◽

Pulmonary Vasodilation ◽

Blocking Voltage ◽

Voltage Dependent ◽

Oxide Synthase

We previously found that alkalosis-induced vasodilation was mediated by endothelium-derived nitric oxide (EDNO) in newborn piglet pulmonary artery and vein rings precontracted with the thromboxane mimetic U-46619. In contrast, prostacyclin or K+ channel activation contributed to the response in other preparations. This study was undertaken to determine whether EDNO alone also mediates alkalosis-induced pulmonary vasodilation in piglet lungs vasoconstricted with hypoxia and, if not, to identify the mediator(s) involved. Responses to alkalosis were measured during hypoxia under control conditions after blocking nitric oxide synthase ( N ω-nitro-l-arginine), cyclooxygenase (meclofenamate), or both endothelium-derived modulators (Dual); after blocking voltage-dependent (4-aminopyridine), ATP- dependent (glibenclamide), or Ca2+-dependent K+ (KCa; tetraethylammonium) K+channels; and after blocking both endothelium-derived modulators and KCa channels (Triple). Vasodilator responses measured after 20 min of alkalosis were blunted in Dual and tetraethylammonium lungs and abolished in Triple lungs. Thus alkalosis-induced vasodilation in hypoxic lungs appeared to be mediated by three Ca2+-dependent modulators: EDNO, prostacyclin, and KCa channels. In addition, a transient, unidentified modulator contributed to the nadir of the vasodilator response measured at 10 min of alkalosis. Future studies are needed to identify factors that contribute to the discordance between isolated vessels and whole lungs.

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