Release of platelet-derived growth factor from human platelets by arachidonic acid

Abstract

Platelet a-granules contain a factor that stimulates the proliferation of arterial smooth muscle cells and may play a role in atherogenesis. We have studied the role of arachidonic acid in mediating the release of the platelet-derived growth factor (PDGF) from human platelets. PDGF was assayed by stimulation of [3Hlthymidine incororation into DNA of mouse 3T3 cells. Platelet aggregation and the release of platelet factor 4, P-thromboglobulin, and serotonin were also studied.A biphasic response pattern was observed when gel-filtered platelets were incubated with arachidonate over the concentration range 0.01-0.4 mM. At low arachidonate levels (approximately 0.025-0.1 mM), specific concentration-dependent aggregation and release of PDGF and of the other components were observed. This effect was not seen with any of five other fatty acids tested and was suppressed by indomethacin (25 uM). At higher arachidonate concentrations (approximately 0.15-0.35 mM), a concentration-dependent turn-off of both aggregation and release occurred. At these concentrations the platelets remained functional, and no release of lactate dehydrogenase was observed. A similar biphasic pattern of arachidonate-induced aggregation and release was observed with platelet-rich plasma, over a similar range of arachidonate to albumin mole ratios. These studies demonstrate that PDGF and other a-granule constituents can be released from platelets specifically by arachidonate via an indomethacin-sensitive pathway, most probably involving the platelet cyclooxygenase and conversion of arachidonate to prostaglandin metabolites. The mechanisms responsible for the turn-off of the specific arachidonate-mediated responses at higher arachidonate concentrations remain to be defined.

Platelets modulate gastric ulcer healing: Role of endostatin and vascular endothelial growth factor release

“…Platelets play a pivotal role in wound healing by releasing a number of growth factors that can promote angiogenesis (5,7,8,29). Therefore, we hypothesized that, in addition to inhibitory effects on platelet aggregation, antiplatelet drugs might impair gastric ulcer healing by virtue of inhibitory effects on growth factor release.…”

“…Platelet aggregation is a cardinal feature of vascular repair. A variety of potent angiogenic stimulators, including VEGF (5), platelet-derived endothelial cell growth factor (6), EGF (7), and platelet-derived growth factor (8), are stored in platelets and released during clotting at the wound. Activation of platelets by ␣-thrombin (9) stimulates angiogenesis in the chick chorioallantoic membrane (10).…”

Thrombin‐induced platelet endostatin release is blocked by a proteinase activated receptor‐4 (PAR4) antagonist

“…A variety of bioactive substances, including growth factors and chemokines (Linder et al, 1979;Maloney et al, 1998;von hundelshausen et al, 2001), are stored in platelets and released during activation. Endostatin, a potent inhibitor of angiogenesis (O'Reilly et al, 1997), has been shown recently to be contained within platelets and to be released in response to thrombin but not to ADP (Ma et al, 2001).…”

“…A variety of other growth factors, including vascular endothelial growth factor, epidermal growth factor and platelet-derived growth factor, are stored in platelet alpha granules and released during platelet aggregation in response to di erent agonists (Linder et al, 1979;Maloney et al, 1998). It is most likely that the release of those factors is due to degranulation during platelet activation and therefore parallels the extent of aggregation (Linder et al, 1979).…”

“…A variety of other growth factors, including vascular endothelial growth factor, epidermal growth factor and platelet-derived growth factor, are stored in platelet alpha granules and released during platelet aggregation in response to di erent agonists (Linder et al, 1979;Maloney et al, 1998). It is most likely that the release of those factors is due to degranulation during platelet activation and therefore parallels the extent of aggregation (Linder et al, 1979). However, although thrombin and ADP induced a similar extent of platelet aggregation in our previous study (Ma et al, 2001), only thrombin stimulated platelet endostatin release, suggesting that endostatin is unlike those growth factors that are stored in alpha granules and released in accordance with the extent of platelet aggregation.…”