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.
Highlights
There is growing evidence that perivascular adipose, a specific visceral fat compartment that surrounds blood vessels with no fascial layer separating it from the vascular wall, may regulate vascular function through paracrine mechanisms, only some of which have been identified [1,2,3,4]
The results presented in the present study unexpectedly reveal that perivascular adipose controls arterial smooth muscle tone by releasing an ‘‘adipose-derived contracting factor’’ (ADCF) formed by COX that becomes functionally relevant in obesity
Monogenic obesity increases perivascular adipose mass 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, 8.361.2 mg/ mm vs. 2.360.4 mg/mm, n = 5–8, p,0.01 vs. control, Figure 1A)
Summary
There is growing evidence that perivascular adipose (commonly referred to as perivascular adipose tissue, PVAT), a specific visceral fat compartment that surrounds blood vessels with no fascial layer separating it from the vascular wall, may regulate vascular function through paracrine mechanisms, only some of which have been identified [1,2,3,4]. Perivascular adipose exerts anticontractile activity [6,7,8,9], which is lost in obesity despite concomitant increases in perivascular adipose mass [8,9,10]. We have previously reported that vasoconstriction due to endothelial cell-derived, cyclooxygenase (COX)-dependent prostanoid formation is enhanced in dietinduced and monogenic models of obesity [12,13,14]. In these previous studies, perivascular adipose had been removed, excluding the possibility of examining its direct effects on vascular tone
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