The Key Role of Caveolin-1 in Estrogen-Mediated Regulation of Endothelial Nitric Oxide Synthase Function in Cerebral Arterioles <i>In vivo</i>

Xu, Huiping; Galea, Elena; Santizo, Roberto A.; Baughman, Verna L.; Pelligrino, Dale A.

doi:10.1097/00004647-200108000-00002

Cited by 47 publications

(56 citation statements)

References 22 publications

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“…It is well known that estrogen exerts its cardioprotective effects rapidly or chronically via nitric oxide, 24,25 and that estrogen regulates nitric oxide synthase function and nitric oxide production through caveolin-1, which is the principle coat protein of caveolae. 26 However, the role of nitric oxide in raloxifene-induced cardioprotection seems to be minimal, because an inhibitor of nitric oxide synthase, L-NAME, did not show significant inhibitory effects of raloxifene. In previous studies, either raloxifene or idoxifene was shown to cause vasorelaxation, mainly in a nitric oxide-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Raloxifene Prevents Cardiac Hypertrophy and Dysfunction in Pressure-Overloaded Mice

Ogita

Node²,

Liao³

et al. 2004

Hypertension

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Abstract-17␤-Estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [ 3 H]leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein (MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [3 H]leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N G -nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent. Key Words: echocardiography Ⅲ heart failure Ⅲ hormones Ⅲ hypertrophy Ⅲ signal transduction T he incidence of left ventricular hypertrophy caused by essential hypertension is one of the major causes of impaired cardiac function followed by heart failure. 1,2 Although the increase in left ventricular mass may represent adaptation of the heart in response to pressure overload, left ventricular hypertrophy is associated with an increased risk of cardiovascular complications and mortality/morbidity. 2-5 Reduction or prevention of left ventricular hypertrophy by treatment with appropriate antihypertensive drugs reduces the risk of cardiovascular diseases or death. 6,7 In postmenopausal women, left ventricular hypertrophy is common and is likely to be a strong cardiovascular risk factor compared with men, suggesting that estrogen has potential protective effects in the cardiovascular system. 2 In fact, hormone replacement therapy in hypertensive postmenopausal women contributes to reducing left ventricular mass, improving cardiac function, and decreasing future cardiovascular events. 8 -10 However, the applicati...

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Section: Discussionmentioning

confidence: 99%

Raloxifene Prevents Cardiac Hypertrophy and Dysfunction in Pressure-Overloaded Mice

Ogita

Node²,

Liao³

et al. 2004

Hypertension

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“…Age-matched female Sprague-Dawley rats (300 -350 g) were used (supplied by Charles River; Wilmington, MA). Pial arteriolar reactivities were evaluated using a closed cranial window and intravital microscopy system (39). The windows were placed on the day preceding study using a procedure described in a previous paper from our laboratory (39).…”

Section: Methodsmentioning

confidence: 99%

“…Pial arteriolar reactivities were evaluated using a closed cranial window and intravital microscopy system (39). The windows were placed on the day preceding study using a procedure described in a previous paper from our laboratory (39). The rats were anesthetized with halothane, intubated, paralyzed with a short-acting muscle relaxant (vecuronium), and mechanically ventilated with a 0.8% halothane-70% N 2O-30% O2 gas mixture.…”

Section: Methodsmentioning

confidence: 99%

“…The brains were then cut into blocks and placed into 4% paraformaldehyde and stored at 4°C until commencement of paraffin embedding. Eight-micrometer coronal sections were prepared from the paraffin-embedded blocks with the use of a microtome (39). The expression of the astrocytic marker protein glial fibrillary acidic protein (GFAP) or nNOS were assessed via immunofluorescence.…”

Section: Methodsmentioning

confidence: 99%

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Influence of the glia limitans on pial arteriolar relaxation in the rat

Xu¹,

Koenig²,

Ye³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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We examined whether damage to the glia limitans (GL), via exposure to the gliotoxin L-␣-aminoadipic acid (L-␣AAA), alters hypercapniainduced pial arteriolar dilation in vivo. Anesthetized female rats were prepared with closed cranial windows. Pial arteriolar diameters were measured using intravital microscopy. L-␣AAA (2 mM) was injected into the space under the cranial windows 24 h before the study, and injury to the GL was confirmed by light microscopy. L-␣AAA was associated with a reduction in pial arteriolar CO 2 reactivity to 40 -50% of the level seen in vehicle-treated controls, with no further reduction in the CO 2 response after nitric oxide (NO) synthase (NOS) inhibition via N -nitro-L-arginine (L-NNA). Subsequent blockade of prostanoid synthesis, via indomethacin (Indo), reduced CO2 reactivity to 10 -15% of normal. In vehicle-treated controls, L-NNA, followed by Indo, reduced the response to ϳ50% and then to 15-20% of the normocapnic value, respectively. On the other hand, L-␣AAA had no effect on vascular responses to the endothelium-dependent vasodilator acetylcholine or the NO donor SNAP and did not alter cortical somatosensory evoked responses. This indicates an absence of any direct L-␣AAA actions on pial arterioles or influence on neuronal transmission. Furthermore, L-␣AAA did not alter the vasodilation elicited by topical application of an acidic artificial cerebrospinal fluid solution, suggesting that the GL influences the pial arteriolar relaxation elicited by hypercapnic, but not local extracellular (EC), acidosis. That differences exist in the mechanisms mediating hypercapniaversus EC acidosis-induced pial arteriolar dilations was further exemplified by the finding that topical application of a neuronal NOS (nNOS)-selective blocker (ARR-17477) reduced the response to hypercapnia (by ϳ65%) but not the response to EC acidosis. Disruption of GL gap junctional communication, using an antisense oligodeoxynucleotide (ODN) connexin43 knockdown approach, was accompanied by a 33% lower CO 2 reactivity versus missense ODN-treated controls. These results suggest that the GL contribution to the hypercapnic vascular response appears to involve the NO-dependent component rather than the prostanoid-dependent component and may involve gap junctional communication. We speculate that the GL may act to facilitate the spread, to pial vessels, of hypercapnia-induced vasodilating signals arising in the comparatively few scattered nNOS neurons that lie well beneath the GL. connexin; gap junction; hypercapnia; L-␣-aminoadipic acid; nitric oxide; prostanoids BECAUSE OF THE INTIMATE ANATOMIC RELATIONSHIP between cerebral resistance vessels and astrocytes (19), it has been postulated that astrocytes play a vital role in the regulation of local perfusion in the brain (7). In fact, experimental evidence to that effect has been published (43). Small pial arterioles (Ͻ50 m), although exhibiting a relative paucity of direct neural connections (8, 33), nevertheless appear to be regulated by extravascular influences (23,38). F...

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“…64 In agreement with this finding, long-term estrogen depletion after ovariectomy is accompanied by an upregulation of (cerebral) endothelial caveolin-1 expression in vivo. 65,66 Ion Channel Regulation Several ion channels have been shown to be associated with caveolae (Table). These channels play a very important role in the regulation of endothelial barrier functioning, because they are involved in the regulation of endothelial cell permeability, transcytosis, angiogenesis, and the response to shear stress.…”

Section: Caveolae Caveolin-1 and Atherosclerosismentioning

confidence: 99%

Caveolin, Caveolae, and Endothelial Cell Function

Frank

Woodman

Park

et al. 2003

ATVB

342

255

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Abstract-Caveolae are 50-to 100-nm cell-surface plasma membrane invaginations observed in terminally differentiated cells. They are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking and signal transduction. The use of caveolin-1-deficient mice has provided many new insights into the roles of caveolae and caveolin-1 in the regulation of endothelial cell function. These novel findings suggest an important role for caveolin-1 in the pathogenesis of cancer, atherosclerosis, and vascular disease.

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The Key Role of Caveolin-1 in Estrogen-Mediated Regulation of Endothelial Nitric Oxide Synthase Function in Cerebral Arterioles In vivo

Cited by 47 publications

References 22 publications

Raloxifene Prevents Cardiac Hypertrophy and Dysfunction in Pressure-Overloaded Mice

Raloxifene Prevents Cardiac Hypertrophy and Dysfunction in Pressure-Overloaded Mice

Influence of the glia limitans on pial arteriolar relaxation in the rat

Caveolin, Caveolae, and Endothelial Cell Function

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