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  • Prostanoids typically act in an autocrine and


    Prostanoids typically act in an autocrine and paracrine fashion by binding to specific receptors in target ceramide to and there is evidence that both PGE2 and prostacyclin may be required for the optimal activation of angiogenesis (Hata and Breyer, 2004). PGE2 and prostacyclin bind to their specific 7-membrane-spanning G-protein-coupled receptors in target cells. Currently, there are four identified receptors for PGE2 (EP1–4) and one for prostacyclin (IP) although the number of prostacyclin receptors is somewhat controversial. In the brain, at least two distinct prostacyclin receptors, designated IP1 (identical to the one expressed by endothelium) and IP2 (found only in the central nervous system), have been identified (Takechi et al., 1996). Considering the lack of general consensus about IP2 existence and the fact that endothelial cells have not been found to express a putative second receptor, what we refer to as IP receptor here should be considered the same as IP1, a name used in some reports. EP receptors differentially activate intracellular signaling mechanisms (Birukova et al., 2007). Thus, EP1 is coupled to the Gq alpha G-protein subunit and mediates the protein kinase C (PKC)-dependent increase in IP3 (inositol 1,4,5-trisphosphate) and Ca++. In contrast, EP2 and EP4 activate Gs, which increases cyclic adenosine monophosphate (cAMP) levels, and EP3 activates Gi, which decreases cAMP concentrations (reviewed in Bos et al., 2004). The IP receptor activates both cAMP synthesis (through Gs subunit activation) and the PKC pathway in a Gq-dependent manner (Bos et al., 2004). EP4 has been found to be most important in the regulation of angiogenesis by PGE2 (Rao et al., 2007, Yanni et al., 2009), whereas pro-angiogenic processes in endothelial cells may be suppressed by IP antagonism (Osawa et al., 2012). Although PGE2 and prostacyclin and their corresponding EP4 and IP receptors clearly exhibit the capacity to regulate angiogenesis, information on their relative contributions is deficient. In the present work we hypothesize that prostacyclin acting through IP receptors is the main activator of pro-angiogenic processes in vascular endothelial cells. To test this hypothesis we have comparatively evaluated the roles of EP and IP receptors on the pro-angiogenic processes (cell migration and blood vessel precursor formation) in primary human endothelial cells (HUVECs).
    Materials and methods
    Discussion In this work we have investigated the regulation by prostanoids of two important angiogenic processes in vitro: endothelial cell migration and the formation of blood vessel precursors, or tubes. While the role of PGE2 in angiogenesis has been well documented, the involvement of prostacyclin is less clear (Spisni et al., 2001, Muramatsu et al., 2012). The major finding to emerge from the present study was that prostacyclin and, to a lesser extent, prostaglandin E2, acting via the corresponding IP and EP4 receptors were important regulators of HUVEC migration and tube formation. Our findings are in accord with present information on the broad involvement of these receptors in vascular physiology, including blood vessel relaxation (Jones and Chan, 2001). The differential regulation of angiogenesis by prostacyclin and PGE2 could be due to either differences in intracellular signaling initiated by prostanoid receptors (Jabbour and Sales, 2004) or expression of IP and EP4 receptors on endothelial cells. While the EP4 receptor selectively activates the Gs-type G-protein subunit, the IP receptor stimulates both Gs and Gq subunits, which increases intracellular cAMP and phosphatidylinositol levels. Thus, Gs could be activated by both EP4 and IP to effect a sustained increase in cAMP, or the selective activation of IP via its Gq subunit could increase intracellular IP3 and Ca++; this would enable complex interplay between the receptors in the regulation of angiogenesis. Furthermore, our findings are consistent with observations that EP4 might be the only EP receptor type expressed in human pulmonary microvascular endothelial cells (Aso et al., 2012). Observed differences in Emax for IP and EP4 antagonists indicate corresponding differences in levels of these two receptors in HUVECs. Therefore, differential response of a given cell type to specific prostanoids could also be a consequence of individual receptor expression. For example, in contrast to our findings in HUVECs, in Wistar–Kyoto rat smooth muscle cells, expression of EP4 receptors is more than 10-fold higher compared to IP expression (Tang and Vanhoutte, 2008).