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Regulation of vascular smooth muscle tone by adipose-derived contracting factor.

Meyer MR, Fredette NC, Barton M, Prossnitz ER - PLoS ONE (2013)

Bottom Line: Inhibition of cyclooxygenase (COX) fully prevented ADCF-mediated contractions, whereas COX-1 or COX-2-selective inhibition was only partially effective.By contrast, inhibition of superoxide anions, NO synthase, or endothelin receptors had no effect on ADCF activity.ADCF may thus propagate obesity-dependent hypertension and the associated increased risk in coronary artery disease, potentially representing a novel therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.

ABSTRACT
Obesity and arterial hypertension, important risk factors for atherosclerosis and coronary artery disease, are characterized by an increase in vascular tone. While obesity is known to augment vasoconstrictor prostanoid activity in endothelial cells, less is known about factors released from fat tissue surrounding arteries (perivascular adipose). Using lean controls and mice with either monogenic or diet-induced obesity, we set out to determine whether and through which pathways perivascular adipose affects vascular tone. We unexpectedly found that in the aorta of obese mice, perivascular adipose potentiates vascular contractility to serotonin and phenylephrine, indicating activity of a factor generated by perivascular adipose, which we designated "adipose-derived contracting factor" (ADCF). Inhibition of cyclooxygenase (COX) fully prevented ADCF-mediated contractions, whereas COX-1 or COX-2-selective inhibition was only partially effective. By contrast, inhibition of superoxide anions, NO synthase, or endothelin receptors had no effect on ADCF activity. Perivascular adipose as a source of COX-derived ADCF was further confirmed by detecting increased thromboxane A2 formation from perivascular adipose-replete aortae from obese mice. Taken together, this study identifies perivascular adipose as a novel regulator of arterial vasoconstriction through the release of COX-derived ADCF. Excessive ADCF activity in perivascular fat under obese conditions likely contributes to increased vascular tone by antagonizing vasodilation. ADCF may thus propagate obesity-dependent hypertension and the associated increased risk in coronary artery disease, potentially representing a novel therapeutic target.

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Perivascular adipose and perigonadal fat mass, body weight and blood pressure in monogenic obesity (GPER0).A, Mass and macroscopic difference in the quantity of perivascular adipose (PVAT) surrounding the aorta (a, Aortic arch; b, Thoracic aorta; c, Abdominal aorta) of obese (GPER0, n = 5) and lean WT control mice (CTL, n = 8). B, Perigonadal fat weight (CTL, n = 8; GPER0, n = 9); C, body weight (n = 19/group); D, systolic and diastolic blood pressure levels in obese (GPER0, , n = 7) and lean WT mice (CTL, , n = 6). Fat weights are normalized to tibial length. A–C: open bars, lean WT control (CTL); solid bars, monogenic obesity (GPER0). *p<0.01 vs. control.
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pone-0079245-g001: Perivascular adipose and perigonadal fat mass, body weight and blood pressure in monogenic obesity (GPER0).A, Mass and macroscopic difference in the quantity of perivascular adipose (PVAT) surrounding the aorta (a, Aortic arch; b, Thoracic aorta; c, Abdominal aorta) of obese (GPER0, n = 5) and lean WT control mice (CTL, n = 8). B, Perigonadal fat weight (CTL, n = 8; GPER0, n = 9); C, body weight (n = 19/group); D, systolic and diastolic blood pressure levels in obese (GPER0, , n = 7) and lean WT mice (CTL, , n = 6). Fat weights are normalized to tibial length. A–C: open bars, lean WT control (CTL); solid bars, monogenic obesity (GPER0). *p<0.01 vs. control.

Mentions: In preliminary experiments with the GPER0 model of monogenic obesity [18], [19], we observed a marked increase in perivascular adipose mass compared with WT controls (3.6-fold increase, adipose mass normalized to tibial length, 8.3±1.2 mg/mm vs. 2.3±0.4 mg/mm, n = 5–8, p<0.01 vs. control, Figure 1A). By contrast, the increase in perigonadal fat mass in GPER0 mice was less pronounced (1.6-fold, normalized to tibial length, 108.6±7.4 vs. 70.8±9.4 mg/mm, n = 8–9, p<0.01 vs. control, Figure 1B). The increase in visceral fat was associated with a significant increase in body weight (41.3±1.2 vs. 36.2±1.2 g, n = 19, p<0.01 vs. lean WT control, Figure 1C), whereas tibial length as a measure of body length was identical in GPER0 and WT control animals (18.6±0.1 mm, n = 5). Obesity (body weight and perivascular adipose) was already present in GPER0 animals at 3 months of age (Figure S1), but by 12 months of age had progressed much further in adult animals (Figure 1). Therefore, 12 month-old animals were selected for vascular function analyses. Despite excessive visceral fat accumulation [18], [27], blood pressure in GPER0 mice remained unchanged compared to controls (systolic, 119.0±0.8 vs. 121.3±1.7 mmHg; diastolic, 90.2±1.3 vs. 89.3±1.9 mmHg; n = 6–7, Figure 1D), consistent with normotensive blood pressure levels measured in the DIO model [21].


Regulation of vascular smooth muscle tone by adipose-derived contracting factor.

Meyer MR, Fredette NC, Barton M, Prossnitz ER - PLoS ONE (2013)

Perivascular adipose and perigonadal fat mass, body weight and blood pressure in monogenic obesity (GPER0).A, Mass and macroscopic difference in the quantity of perivascular adipose (PVAT) surrounding the aorta (a, Aortic arch; b, Thoracic aorta; c, Abdominal aorta) of obese (GPER0, n = 5) and lean WT control mice (CTL, n = 8). B, Perigonadal fat weight (CTL, n = 8; GPER0, n = 9); C, body weight (n = 19/group); D, systolic and diastolic blood pressure levels in obese (GPER0, , n = 7) and lean WT mice (CTL, , n = 6). Fat weights are normalized to tibial length. A–C: open bars, lean WT control (CTL); solid bars, monogenic obesity (GPER0). *p<0.01 vs. control.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3823600&req=5

pone-0079245-g001: Perivascular adipose and perigonadal fat mass, body weight and blood pressure in monogenic obesity (GPER0).A, Mass and macroscopic difference in the quantity of perivascular adipose (PVAT) surrounding the aorta (a, Aortic arch; b, Thoracic aorta; c, Abdominal aorta) of obese (GPER0, n = 5) and lean WT control mice (CTL, n = 8). B, Perigonadal fat weight (CTL, n = 8; GPER0, n = 9); C, body weight (n = 19/group); D, systolic and diastolic blood pressure levels in obese (GPER0, , n = 7) and lean WT mice (CTL, , n = 6). Fat weights are normalized to tibial length. A–C: open bars, lean WT control (CTL); solid bars, monogenic obesity (GPER0). *p<0.01 vs. control.
Mentions: In preliminary experiments with the GPER0 model of monogenic obesity [18], [19], we observed a marked increase in perivascular adipose mass compared with WT controls (3.6-fold increase, adipose mass normalized to tibial length, 8.3±1.2 mg/mm vs. 2.3±0.4 mg/mm, n = 5–8, p<0.01 vs. control, Figure 1A). By contrast, the increase in perigonadal fat mass in GPER0 mice was less pronounced (1.6-fold, normalized to tibial length, 108.6±7.4 vs. 70.8±9.4 mg/mm, n = 8–9, p<0.01 vs. control, Figure 1B). The increase in visceral fat was associated with a significant increase in body weight (41.3±1.2 vs. 36.2±1.2 g, n = 19, p<0.01 vs. lean WT control, Figure 1C), whereas tibial length as a measure of body length was identical in GPER0 and WT control animals (18.6±0.1 mm, n = 5). Obesity (body weight and perivascular adipose) was already present in GPER0 animals at 3 months of age (Figure S1), but by 12 months of age had progressed much further in adult animals (Figure 1). Therefore, 12 month-old animals were selected for vascular function analyses. Despite excessive visceral fat accumulation [18], [27], blood pressure in GPER0 mice remained unchanged compared to controls (systolic, 119.0±0.8 vs. 121.3±1.7 mmHg; diastolic, 90.2±1.3 vs. 89.3±1.9 mmHg; n = 6–7, Figure 1D), consistent with normotensive blood pressure levels measured in the DIO model [21].

Bottom Line: Inhibition of cyclooxygenase (COX) fully prevented ADCF-mediated contractions, whereas COX-1 or COX-2-selective inhibition was only partially effective.By contrast, inhibition of superoxide anions, NO synthase, or endothelin receptors had no effect on ADCF activity.ADCF may thus propagate obesity-dependent hypertension and the associated increased risk in coronary artery disease, potentially representing a novel therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.

ABSTRACT
Obesity and arterial hypertension, important risk factors for atherosclerosis and coronary artery disease, are characterized by an increase in vascular tone. While obesity is known to augment vasoconstrictor prostanoid activity in endothelial cells, less is known about factors released from fat tissue surrounding arteries (perivascular adipose). Using lean controls and mice with either monogenic or diet-induced obesity, we set out to determine whether and through which pathways perivascular adipose affects vascular tone. We unexpectedly found that in the aorta of obese mice, perivascular adipose potentiates vascular contractility to serotonin and phenylephrine, indicating activity of a factor generated by perivascular adipose, which we designated "adipose-derived contracting factor" (ADCF). Inhibition of cyclooxygenase (COX) fully prevented ADCF-mediated contractions, whereas COX-1 or COX-2-selective inhibition was only partially effective. By contrast, inhibition of superoxide anions, NO synthase, or endothelin receptors had no effect on ADCF activity. Perivascular adipose as a source of COX-derived ADCF was further confirmed by detecting increased thromboxane A2 formation from perivascular adipose-replete aortae from obese mice. Taken together, this study identifies perivascular adipose as a novel regulator of arterial vasoconstriction through the release of COX-derived ADCF. Excessive ADCF activity in perivascular fat under obese conditions likely contributes to increased vascular tone by antagonizing vasodilation. ADCF may thus propagate obesity-dependent hypertension and the associated increased risk in coronary artery disease, potentially representing a novel therapeutic target.

Show MeSH
Related in: MedlinePlus