Vascular mechanisms of increased arterial pressure in  preeclampsia: lessons from animal models

Normal pregnancy is associated with reductions in total vascular resistance and arterial pressure possibly due to enhanced endothelium-dependent vascular relaxation and decreased vascular reactivity to vasoconstrictor agonists. These beneficial hemodynamic and vascular changes do not occur in women who develop preeclampsia; instead, severe increases in vascular resistance and arterial pressure are observed. Although preeclampsia represents a major cause of maternal and fetal morbidity and mortality, the vascular and cellular mechanisms underlying this disorder have not been clearly identified. Studies in hypertensive pregnant women and experimental animal models suggested that reduction in uteroplacental perfusion pressure and the ensuing placental ischemia/hypoxia during late pregnancy may trigger the release of placental factors that initiate a cascade of cellular and molecular events leading to endothelial and vascular smooth muscle cell dysfunction and thereby increased vascular resistance and arterial pressure. The reduction in uterine perfusion pressure and the ensuing placental ischemia are possibly caused by inadequate cytotrophoblast invasion of the uterine spiral arteries. Placental ischemia may promote the release of a variety of biologically active factors, including cytokines such as tumor necrosis factor-α and reactive oxygen species. Threshold increases in the plasma levels of placental factors may lead to endothelial cell dysfunction, alterations in the release of vasodilator substances such as nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor, and thereby reductions of the NO-cGMP, PGI2-cAMP, and hyperpolarizing factor vascular relaxation pathways. The placental factors may also increase the release of or the vascular reactivity to endothelium-derived contracting factors such as endothelin, thromboxane, and ANG II. These contracting factors could increase intracellular Ca2+concentrations ([Ca2+]i) and stimulate Ca2+-dependent contraction pathways in vascular smooth muscle. The contracting factors could also increase the activity of vascular protein kinases such as protein kinase C, leading to increased myofilament force sensitivity to [Ca2+]i and enhancement of smooth muscle contraction. The decreased endothelium-dependent mechanisms of vascular relaxation and the enhanced mechanisms of vascular smooth muscle contraction represent plausible causes of the increased vascular resistance and arterial pressure associated with preeclampsia.

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Gender-related distinctions in protein kinase C activity in rat vascular smooth muscle

AJP Cell Physiology ◽

10.1152/ajpcell.2001.280.1.c34 ◽

2001 ◽

Vol 280 (1) ◽

pp. C34-C45 ◽

Cited By ~ 66

Author(s):

Celia A. Kanashiro ◽

Raouf A. Khalil

Keyword(s):

Gender Differences ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Vascular Reactivity ◽

Smooth Muscle Contraction ◽

Intact Male ◽

Western Blots ◽

Wky Rats ◽

Pkc Isoforms ◽

17Β Estradiol

Gender differences in vascular reactivity have been suggested; however, the cellular mechanisms involved are unclear. We tested the hypothesis that the gender differences in vascular reactivity reflect gender-related, possibly estrogen-mediated, distinctions in the expression and activity of specific protein kinase C (PKC) isoforms in vascular smooth muscle. Aortic strips were isolated from intact and gonadectomized male and female Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Isometric contraction was measured in endothelium-denuded aortic strips. PKC activity was measured in the cytosolic and particulate fractions, and the amount of PKC was measured using Western blots and isoform-specific anti-PKC antibodies. In intact male WKY rats, phenylephrine (Phe, 10−5 M) and phorbol 12,13-dibutyrate (PDBu, 10−6 M) stimulated contraction to 0.37 ± 0.02 and 0.42 ± 0.02 g/mg tissue wt, respectively. The basal particulate/cytosolic PKC activity ratio was 0.86 ± 0.06, and Western blots revealed α-, δ-, and ζ-PKC isoforms. Phe and PDBu increased PKC activity and caused significant translocation of α- and δ-PKC from the cytosolic to particulate fraction. In intact female WKY rats, basal PKC activity, the amount of α-, δ-, and ζ-PKC, the Phe- and PDBu-induced contraction, and PKC activity and translocation of α- and δ-PKC were significantly reduced compared with intact male WKY rats. The basal PKC activity, the amount of α-, δ-, and ζ-PKC, the Phe and PDBu contraction, and PKC activity and α- and δ-PKC translocation were greater in SHR than WKY rats. The reduction in Phe and PDBu contraction and PKC activity in intact females compared with intact males was greater in SHR (∼30%) than WKY rats (∼20%). Phe and PDBu contraction and PKC activity were not significantly different between castrated males and intact males but were greater in ovariectomized (OVX) females than intact females. Treatment of OVX females or castrated males with 17β-estradiol, but not 17α-estradiol, subcutaneous implants caused significant reduction in Phe and PDBu contraction and PKC activity that was greater in SHR than WKY rats. Phe and PDBu contraction and PKC activity in OVX females or castrated males treated with 17β-estradiol plus the estrogen receptor antagonist ICI-182,780 were not significantly different from untreated OVX females or castrated males. Thus a gender-related reduction in vascular smooth muscle contraction in female WKY rats with intact gonads compared with males is associated with reduction in the expression and activity of vascular α-, δ-, and ζ-PKC. The gender differences in vascular smooth muscle contraction and PKC activity are augmented in the SHR and are possibly mediated by estrogen.

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Attenuation of vascular relaxation after development of tachyphylaxis to peroxynitrite in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.275.2.h501 ◽

1998 ◽

Vol 275 (2) ◽

pp. H501-H508 ◽

Cited By ~ 9

Author(s):

Nancy A. Benkusky ◽

Stephen J. Lewis ◽

Neil W. Kooy

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Mean Arterial Pressure ◽

Arterial Pressure ◽

Vascular Smooth Muscle ◽

Rapid Development ◽

Nitric Oxide Donor ◽

Vascular Relaxation ◽

Diffusion Limited

Peroxynitrite, formed endogenously by the near diffusion-limited reaction of nitric oxide with superoxide anion, induces vascular relaxation. This effect is subject to rapid tachyphylaxis, suggesting that peroxynitrite may alter subsequent vasorelaxant responses. The present study examined the effects of peroxynitrite on mean arterial pressure and hindquarter, renal, and mesenteric vascular resistances in pentobarbital-anesthetized rats. Peroxynitrite induced dose-dependent decreases in mean arterial pressure and hindquarter and mesenteric vascular resistances. The repetitive administration of peroxynitrite resulted in the rapid development of tachyphylaxis, with subsequent doses producing progressively smaller effects. After the development of tachyphylaxis to peroxynitrite, the hemodynamic effects produced by the systemic administration of acetylcholine and prostacyclin were significantly attenuated, whereas the hemodynamic responses to bradykinin and the nitric oxide donor ( Z)-1-{ N-methyl- N-[6( N-methylammoniohexyl)amino]}diazen-1-ium-1,2-diolate (MAHMA NONOate) remained unchanged. These results demonstrate that 1) peroxynitrite is a potent vasorelaxant in vivo, 2) peroxynitrite-mediated vasodilatation is subject to the development of rapid tachyphylaxis, and 3) peroxynitrite alters the vascular smooth muscle response to prostacyclin, perhaps via inactivation of vascular smooth muscle ATP-sensitive potassium channel function.

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Vascular smooth muscle-specific deletion of the leptin receptor attenuates leptin-induced alterations in vascular relaxation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00336.2015 ◽

2016 ◽

Vol 310 (10) ◽

pp. R960-R967 ◽

Cited By ~ 4

Author(s):

Michael J. Ryan ◽

T. Taylor Coleman ◽

Jennifer M. Sasser ◽

Katarina M. Pittman ◽

Michael W. Hankins ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Vascular Reactivity ◽

Leptin Receptor ◽

Physiological Role ◽

Vascular Relaxation ◽

Leptin Receptors ◽

Significant Impairment ◽

Significant Attenuation ◽

Relaxation Responses

Obesity is a risk factor for cardiovascular disease and is associated with increased plasma levels of the adipose-derived hormone leptin. Vascular smooth muscle cells (VSMC) express leptin receptors (LepR); however, their physiological role is unclear. We hypothesized that leptin, at levels to mimic morbid obesity, impairs vascular relaxation. To test this, we used control and VSM-LepR knockout mice (VSM-LepR KO) created with a tamoxifen-inducible specific Cre recombinase to delete the LepR gene in VSMC. Control (10–12 wk old) and VSM-LepR KO (10–12 wk old) mice were fed a diet containing tamoxifen (50 mg/kg) for 6 wk, after which vascular reactivity was studied in isolated carotid arteries using an organ chamber bath. Vessels were incubated with leptin (100 ng/ml) or vehicle (0.1 mM Tris·HCl) for 30 min. Leptin treatment resulted in significant impairment of vessel relaxation to the endothelial-specific agonist acetylcholine (ACh). When these experiments were repeated in the presence of the superoxide scavenger tempol, relaxation responses to ACh were restored. VSM-LepR deletion resulted in a significant attenuation of leptin-mediated impaired ACh-induced relaxation. These data show that leptin directly impairs vascular relaxation via a VSM-LepR-mediated mechanism, suggesting a potential pathogenic role for leptin to increase cardiovascular risk during obesity.

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Calcium and Vascular Smooth Muscle Contraction

Circulation Research ◽

10.1161/01.res.28.5_suppl_2.ii-88 ◽

1971 ◽

Vol 28 (5 Suppl 2) ◽

pp. II-88-II-95 ◽

Cited By ~ 23

Author(s):

CHARLES L. SEIDEL ◽

DAVID F. BOHR

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Muscle Contraction ◽

Smooth Muscle Contraction ◽

Vascular Smooth Muscle Contraction

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Mechanisms of Direct Inhibitory Action of Isoflurane on Vascular Smooth Muscle of Mesenteric Resistance Arteries

Anesthesiology ◽

10.1097/00000542-200309000-00023 ◽

2003 ◽

Vol 99 (3) ◽

pp. 666-677 ◽

Cited By ~ 18

Author(s):

Takashi Akata ◽

Tomoo Kanna ◽

Jun Yoshino ◽

Shosuke Takahashi

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Vascular Reactivity ◽

Channel Blocker ◽

Isometric Force ◽

Systemic Resistance ◽

Resistance Arteries ◽

Voltage Gated ◽

Fura 2 ◽

Force Relation

Background Isoflurane has been shown to directly inhibit vascular reactivity. However, less information is available regarding its underlying mechanisms in systemic resistance arteries. Methods Endothelium-denuded smooth muscle strips were prepared from rat mesenteric resistance arteries. Isometric force and intracellular Ca2+ concentration ([Ca2+]i) were measured simultaneously in the fura-2-loaded strips, whereas only the force was measured in the beta-escin membrane-permeabilized strips. Results Isoflurane (3-5%) inhibited the increases in both [Ca2+]i and force induced by either norepinephrine (0.5 microM) or KCl (40 mM). These inhibitions were similarly observed after depletion of intracellular Ca2+ stores by ryanodine. Regardless of the presence of ryanodine, after washout of isoflurane, its inhibition of the norepinephrine response (both [Ca2+]i and force) was significantly prolonged, whereas that of the KCl response was quickly restored. In the ryanodine-treated strips, the norepinephrine- and KCl-induced increases in [Ca2+]i were both eliminated by nifedipine, a voltage-gated Ca2+ channel blocker, whereas only the former was inhibited by niflumic acid, a Ca2+-activated Cl- channel blocker. Isoflurane caused a rightward shift of the Ca2+-force relation only in the fura-2-loaded strips but not in the beta-escin-permeabilized strips. Conclusions In mesenteric resistance arteries, isoflurane depresses vascular smooth muscle reactivity by directly inhibiting both Ca2+ mobilization and myofilament Ca2+ sensitivity. Isoflurane inhibits both norepinephrine- and KCl-induced voltage-gated Ca2+ influx. During stimulation with norepinephrine, isoflurane may prevent activation of Ca2+-activated Cl- channels and thereby inhibit voltage-gated Ca2+ influx in a prolonged manner. The presence of the plasma membrane appears essential for its inhibition of the myofilament Ca2+ sensitivity.

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