Sex differences in the role of phospholipase A2 -dependent arachidonic acid pathway in the perivascular adipose tissue function in pigs.

KEY POINTS: The fat surrounding blood vessels (perivascular adipose tissue or PVAT) releases vasoactive compounds that regulate vascular smooth muscle tone. There are sex differences in the regulation of vascular tone, but, to date, no study has investigated whether there are sex differences in the regulation of blood vessel tone by PVAT. This study has identified that the cyclooxygenase products thromboxane and PGF2α are released from coronary artery PVAT from pigs. Thromboxane appears to mediate the PVAT-induced contraction in arteries from females, whereas PGF2α appears to mediate the contraction in arteries from males. These sex differences in the role of these prostanoids in the PVAT-induced contraction can be explained by a greater release of thromboxane from PVAT from female animals and greater sensitivity to PGF2α in the porcine coronary artery from males. ABSTRACT: Previous studies have demonstrated that perivascular adipose tissue (PVAT) causes vasoconstriction. In this present study, we determined the role of cyclooxygenase-derived prostanoids in this contractile response and determined whether there were any sex differences in the regulation of vascular tone by PVAT. Contractions in isolated segments of coronary arteries were determined using isolated tissue baths and isometric tension recording. Segments were initially cleaned of PVAT, which was then re-added to the tissue bath and changes in tone measured over 1 h. Levels of PGF2α and thromboxane B2 (TXB2 ) were quantified by ELISA, and PGF2α (FP) and thromboxane A2 (TP) receptor expression determined by Western blotting. In arteries from both male and female pigs, re-addition of PVAT caused a contraction, which was partially inhibited by the cyclooxygenase inhibitors indomethacin and flurbiprofen. The FP receptor antagonist AL8810 attenuated the PVAT-induced contraction in arteries from males, whereas the TP receptor antagonist GR32191B inhibited the PVAT-induced contraction in arteries from females. Although there was no difference in PGF2α levels in PVAT between females and males, PGF2α produced a larger contraction in arteries from males, correlating with a higher FP receptor expression. In contrast, release of TXB2 from PVAT from females was greater than from males, but there was no difference in the contraction by the TXA2 agonist U46619, or TP receptor expression in arteries from different sexes. These findings demonstrate clear sex differences in PVAT function in which PGF2α and TXA2 antagonists can inhibit the PVAT-induced vasoconstriction in male and female PCAs, respectively.

Sex differences in the regulation of porcine coronary artery tone by perivascular adipose tissue: a role of adiponectin?

BACKGROUND AND PURPOSE: As there is sexual dimorphism in the regulation of vascular tone, the aim of this present study was to determine whether there are sex differences in perivascular adipose tissue (PVAT)-mediated regulation of the porcine coronary artery (PCA) tone. EXPERIMENTAL APPROACH: Isometric tension recording system was used to record changes in tone in PCAs. Western blot analysis was performed to examine the expression of adiponectin in PVAT and adiponectin receptors and adiponectin binding protein (APPL1) in PCA. The level of adiponectin released from PVAT was measured using elisa. KEY RESULTS: In the presence of adherent PVAT, contractions to the thromboxane mimetic U46619 and endothelin-1 were significantly reduced in PCAs from females, but not males. In PCAs pre-contracted with U46619, re-addition of PVAT caused relaxation in PCAs from females, but not males. This relaxant response in females was attenuated by combined inhibition of NOS (with L-NAME) and COX (with indomethacin). Pre-incubation with an anti-adiponectin antibody abolished the relaxant effects of PVAT. The adiponectin receptor agonist (adipoRon) produced a greater relaxation in PCAs from females compared with males. However, there was no difference in either the expression or release of adiponectin from PVAT between sexes. Similarly, there was no difference in the expression of adiponectin receptors or the adiponectin receptor adaptor protein APPL1 in PCAs. CONCLUSION AND IMPLICATIONS: These findings demonstrate a clear sex difference in the regulation of coronary arterial tone in response to adiponectin receptor stimulation, which may underlie the anticontractile effects of PVAT in females.