| Summary: | Lysophosphatidylcholine (1-acyl-sn-glycero-3-phosphocholine, LPC) is the most abundant glycerol-based lysophospholipid present in cell membranes and oxidized lipoproteins. It has been proposed that LPC contributes to the altered vaso-reactivity associated with various cardiovascular diseases in which elevated LPC levels were identified. However, the contribution of LPC in regulating vascular resistance has not been completely elucidated, as the majority of previous studies have used either large blood vessels or isolated cells. Therefore, our study aimed to investigate the vasoactive effects and the underlying mechanisms of LPC in small arteries/arterioles that are crucial in the determination of vascular resistance and the maintenance of organ function.
The unique finding of our investigation is that LPC possesses biphasic effects on both peripheral arterial resistance and coronary circulation, and even ventricular function. Specifically, in the isolated perfused rat mesenteric arterial bed, both endothelium-derived relaxing factors and thromboxane A₂ (TxA₂, a vasoconstricor) are diminished by LPC perfusion. However, LPC washout stimulates a rebound overproduction of TxA₂, which results in an enhanced contractile response to alpha1-adrenoceptor stimulation.
Our study next found that sustained perfusion of hearts with LPC augmented coronary perfusion pressure and reduced left ventricular developed pressure. These effects were exaggerated when LPC was removed from the perfusate. Furthermore, LPC selectively potentiated the receptor-coupled vasoconstrictor response of isolated rat septal coronary artery to U-46619, a TxA₂ mimetic. Interestingly, when LPC was washed out, the potentiation to U-46619 was even more pronounced. Both the immediate and residual effects of LPC were endothelium-dependent. Endothelium-derived hyperpolarizing factor was likely the sole mediator responsible for the direct effects of LPC on U-46619-vasoconstriction, whereas the augmented vasoconstrictor responses following LPC washout may in part be related to an increase in endothelin-1, and a striking reduction in the bioavailability of nitric oxide.
Our data suggest that simply reducing LPC levels to normal may not be sufficient to reverse the adverse consequences of this lysolipid accumulation in vasculature. Further understanding of the residual effects of LPC will enable the identification of more effective treatment targets for LPC-related diseases.
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