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

Multiple transferable substances released from perivascular adipose tissue (PVAT) play an important role in the modulation of vascular smooth muscle contraction. Here, sex differences in PVAT function, particularly the role of phospholipase A2-dependent arachidonic acid pathway (PLA2-AA), in isolated porcine coronary arteries (PCAs) were investigated.

An isometric tension recording system was used to record the vessel responses in the presence of a range of inhibitors with and without PVATincubation for an hour. Levels of PGF2-α and thromboxane B2 (TXB2) were quantified spectrophotometrically by ELISA whereas level of expression of PGF2-α (FP) and thromboxane A2 (TP) receptors were determined by Western blotting. Data are expressed as mean ± S.E.M and analysed using 2-tailed, paired or unpaired Student’s t-test to compare differences between 2 groups. Differences between 3 or more groups were assessed using two-way ANOVA in conjunction with the Sidak’spost-hoc testto assess possible difference at individual concentrations.

Addition of PVAT (0.3g) caused a gradual and significant increase in vascular tone over an hour in female and male PCAs (n=7-4, P>0.001). In PCAs from both sexes, treatment of the vessels with PLA2 stimulator (melittin) (10µM) enhanced the PVAT-induced vasoconstriction(n=5-8, P>0.001) while cyclooxygenase inhibitors (indomethacin(10µM)and flurbiprofen(10µM)) reduced it (n=15-8, P>0.001). Pre-incubation with the FPreceptor antagonist (AL8810) (10µM)and TPreceptor antagonist (GR32191B) (3µM)caused inhibition of the contractile response to PVAT in male and female arteries, respectively. ELISA did not detect a difference in PGF2-α levels and TXB2 between female and male PVAT (PGF2-a: 4.49 ± 0.27pg/ml/µg protein, females; 5.26 ± 0.94pg/ml/µg protein, males) (TXB2: 5.8 ± 0.8pg/ml/µg protein, females; 5.6 ± 0.8pg/ml/µg protein, males). Reactivity of the PCAs to PGF2-α (1µM)was greater in males than females (male: Rmax= 19.83 ± 3.88%; Female:Rmax=11.54 ± 1.38%) whereas the contractile response to TXA2 agonist (U46619) (1nM-300nM) was similar in male and female PCAs. FP receptor expression was greater in PCAs from males (for FP receptor to MLC %, 3 ± 0.6, females and 6.2 ± 0.7, males)while TP receptor expression was about the same in PCAs from different sexes. However, release of TXB2 from female PVAT was greater than from male PVAT (n=10-9, P=0.02).

In summary, these findings suggest that there are clear sex differences in PVAT function in which, under physiological conditions, PGF2-α and TXA2 are responsible for vasoconstriction induced by PVAT in male and female PCAs, respectively. This variation could be explained by differences in the release of TXB2 from PVAT and the responsiveness of PCAs to PGF2-α rather than their expression in PVAT in different sexes.

(1) Szasz, T et al. (2013). Vasc Health Risk Manag 9: 105-116.