Cardiovascular Pharmacology: Open Access

Many metabolic diseases including hypertension, diabetes, atherosclerosis, or stroke are associated with alterations in the function of arteries. Reduced dilations or increased contractions have been found in different vascular beds of many animal models of these metabolic diseases. It is known that premenopausal women tend to have less metabolic diseases than age-matched men do. Gender-related differences in arterial tone have been observed in both animals and humans, which is summarized in Table 1 [1,2].

Table 1: Summary of gender differences in arterial tone in animals and humans.

Wire myography and pressure myography have been frequently used to investigate in vitro vasoconstriction or vasodilation to different agonists. Wire myography was developed in 1977 by Mulvany and Halpern to study the vascular responses of isolated small arteries [3,4]. Vessel rings are mounted through two parallel wires clamped at both ends. A micrometric screw is used to adjust the distance between the two wires, and a force transducer is used to record the isometric tension. With this method several arteries can be investigated simultaneously. Pressure myography was a method first introduced by Duling et al. in 1981 [5]. Vessel segments are cannulated at both ends with small glass pipettes and secured with sutures. During the experimental period vessel diameter changes can be measured continuously. Arteries under the more physiological isobaric conditions had higher sensitivity to noradrenaline than similar ones under isometric conditions [6,7].

Estrogen and Prostanoids

Estrogen may modulate cross-talk between NO and prostanoids derived from NOS and cyclooxygenase respectively. Estradiol stimulated endothelial prostaglandin I₂ release through ERα [20-23]. In human endothelial cells estradiol inhibited thromboxane A₂ production under pro-inflammatory conditions, an effect mediated by GPER. Morever, in mouse carotid arteries endogenous estrogen blocked prostanoid-dependent vasoconstriction through GPER [24].

Estrogen and [Ca²⁺]_i

The effects of estrogen on NO production appeared to be related to [Ca²⁺]_i in the vascular smooth muscle and endothelium. Endogenous estrogen bound GPER which then led to inhibition of ET-1-stimulated increase in [Ca²⁺]_i [25]. This was in accordance with previous observation that 17β-estradiol reduced VSMC [Ca²⁺]_i increases mediated by phenylephrine [26]. Experiments on uterine arteries of rats suggested estrogen replacement was associated with ACh-induced enhancement of endothelial [Ca²⁺]_i [27].

Estrogen and Protein Kinase C (PKC)

Treatment with estradiol caused downregulation of PKC signaling in sheep uterine arteries [28], which may provide an understanding of the mechanisms in estrogen regulation of vascular tone.

Although many factors have been shown to be the downstream targets of estrogen, this review will focus on the role of Phospholipase A2 group 1B (PLA2G1B) in gender-related differences in vascular function.

Role of PLA2G1B in Metabolic Diseases

Inactivation or pharmacological inhibition of the PLA2G1B gene suppressed diet-induced hyperlipidemia, atherosclerosis, obesity and diabetes in mice [29-31]. Moreover, PLA2G1B over-expression in pancreatic acinar cells promoted obesity and diabetes in transgenic mice [32]. So inhibition of the bioavailability of PLA2G1B may be a promising therapeutic target to prevent these metabolic diseases.

Role of PLA2G1B in Gender Differences

Eyster et al. firstly discovered in mesenteric arteries of rats the gene expression of PLA2G1B was significantly up-regulated by counteracting estrogen, whereas that of cPLA2 was not affected by it [33]. But in cultured rat ovaries inhibiting estrogen decreased PLA2G1B expression [34]. As reported recently, the PLA2G1B gene was markedly down-regulated in trigeminal ganglia of female rats exposed to nerve injury but not in males [35]. The observations suggest that PLA2G1B might be involved in gender-related differences in vascular function as well.

General Properties of PLA2G1B

The PLA2G1B is a secreted extracellular phospholipase A₂ with Ca²⁺ binding sites. It is highly expressed in the acinar cells of the pancreas and to lesser extent in the lung and islet β-cells. So PLA2G1B has been thought to participate in hydrolysis of phospholipids in the digestive tract. PLA2G1B inhibition may protect against diet-induced metabolic diseases [36].

Considering its presence in arteries [33], PLA2G1B may play an important role in gender-related differences in vascular function as follows: together with its “bottleneck” activation of cytosolic PLA2cPLA2, PLA2G1B can act on membrane phospholipids of endothelial cells to release arachidonic acid, thereby resulting in production of prostaglandins (Figure 1) [37,38]. Thromboxane A2, prostaglandin D2, prostaglandin E2, prostaglandin F2α, or high concentration of prostaglandin I2 can cause vascular smooth muscle constriction through TxA2/prostanoid receptors [39,40]. Thereforeestrogen may decrease agonist-induced vasoconstriction through inhibiting PLA2G1B activity. Recent observation showed that the upregulated cPLA2 phosphorylation (not cPLA2) and subsequently increased prostaglandin F2α release were involved in endothelium-dependent contractions of aorta from hypertensive mice, which was mediated by PKC activation. Nevertheless, the expressions of PLA2G1B were not investigated in this study [41].

Figure 1:Postulated mechanism of gender-related differences in vascular function by which estrogen inhibiting PLA2G1B activity. PLA2G1B regulates the “bottleneck” phosphorylation of cPLA₂, hydrolyse membrane phospholipids to form arachidonic acid, thereby resulting in production of vasoconstrictor prostaglandins. EC, endothelial cell; VSMC, vascular smooth muscle cell; Phospholipase A₂ group 1_B, PLA2G1B; cytosolic PLA₂, cPLA₂. →stimulate; ―l, inhibit.

Premenopausal women were at lower risk of hypertension, diabetes, atherosclerosis, or stroke than men of the same age. Agonist-induced endothelium-dependent constriction was significantly greater in arteries of male animals than that in female ones. Vascular protective effects of the female sex hormone estrogen have been suggested in this gender difference. Many factors, such as NO, prostaglandins, [Ca²⁺]_i and so on, have been related to vascular effects of estrogen. Inactivation of the PLA2G1B gene suppressed diet-induced metabolic diseases in mice, whereas PLA2G1B over-expression in pancreatic acinar cells promoted these diseases in transgenic mice. Regarding its presence in arteries, PLA2G1B may play an important role in genderrelated differences in vascular function. Pharmacological inhibition of PLA2G1B may offer an attractive avenue for clinical intervention of metabolic diseases in men or menopausal women.