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M. FRESNO Y COLS. AN. R. ACAD. NAC. FARM

Among eicosanoids, TXA2 and PGI2 are thought to be the most
important prostanoids in controlling the homeostasis of the cardiovascular
system, as proposed more than 20 years ago by Bunting, Moncada and
Vane (5, 50, 51). They are synthesized by blood platelets and vascular
endothelium, respectively, and have opposed biological activities. TXA2
is potent vasoconstrictor as well as a potent inducer of platelet adhesion
and regulates renal hemodynamics and sodium handling by the kidney
(4). On the other hand, PGI2 is the predominant prostanoid produced by
cells of the vasculature, having an important vasodilator effect by
promoting renal sodium excretion and regulating the growth of vascular
smooth muscle cells. Moreover, it opposes TXA2 effects on platelets
inhibiting their aggregation and action (28, 52).

Due to this, many aspects of cardiovascular disease have
traditionally been explained by alterations in the balance between PGI2
and TXA2 during the interactions between platelets and vessel wall (53)
although recent studies argue about this theory (54). Since platelets
express COX-1 but not COX-2, it is inferred that TXA2 production by
TXAS uses PGH2 derived from COX-1. In this regard, platelet TXA2 is
blunted in COX-1 deficient mice, which have decreased platelet
aggregation and thrombosis (55). Mice deficient in the TP (51, 56) or
human patients with a genetic disorder in the TP receptor (57, 58) exhibit
an increase in bleeding tendency and resistance to platelet aggregation,
confirming the role of TXA2 in those activities and consistent with the
effects of TP antagonists in humans. Conversely, transgenic mice
specifically overexpressing TP in the vasculature results in placental
ischemia during pregnancy and suppression of TXA2 formation rescue the
phenotype (59). Since TXA2 is a mitogen of vascular smooth muscle
cells, TP KO mice have decreased vascular proliferation and platelet
response after artery injury to the carotid although they are normotensive
(51).

Whether PGI2 is synthesized through COX-1 or COX-2 has been
of paramount importance in classical cardiovascular research. Initial
reports indicated that vascular endothelial cells and smooth muscle cells
have COX-1, and that PGI2 can be formed through COX-1 which was
supported by the fact that in endothelial cells, PGIS co-localizes with

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