The Proangiogenic Phenotype of Tumor-Derived Endothelial Cells is Reverted by the Overexpression of Platelet-Activating Factor Acetylhydrolase

Abstract

Purpose: We previously reported that human tumor-derived endothelial cells (TEC) have an angiogenic phenotype related to the autocrine production of several angiogenic factors. The purpose of the present study was to evaluate whether an enhanced synthesis of plateletactivating factor (PAF) might contribute to the proangiogenic characteristics of TEC and whether its inactivation might inhibit angiogenesis. Experimental Design: To address the potential role of PAF in the proangiogenic characteristics of TEC, we engineered TEC to stably overexpress human plasma PAF-acetylhydrolase (PAF-AH), the major PAF-inactivating enzyme, and we evaluated in vitro and in vivo angiogenesis. Results: TECs were able to synthesize a significantly enhanced amount of PAF compared with normal human microvascular endothelial cells when stimulated with thrombin, vascular endothelial growth factor, or soluble CD154. Transfection of TEC with PAF-AH (TEC-PAF-AH) significantly inhibited apoptosis resistance and spontaneous motility of TEC. In addition, PAF and vascular endothelial growth factor stimulation enhanced the motility and adhesion of TEC but not of TEC-PAF-AH. In vitro, TEC-PAF-AH lost the characteristic ability of TEC to form vessel-like structures when plated on Matrigel. Finally, when cells were injected s.c. within Matrigel in severe combined immunodeficiency mice or coimplanted with a renal carcinoma cell line, the overexpression of PAF-AH induced a significant reduction of functional vessel formation. Conclusions: These results suggest that inactivation of PAF, produced by TEC, by the overexpression of plasma PAF-AH affects survival, migration, and the angiogenic response of TEC both in vitro and in vivo.

The immunomodulatory potential of Leonurus cardiaca extract in relation to endothelial cells and platelets

“…43,51 Numerous studies have demonstrated that tumours and cancer cell lines also synthesize and secrete PAF, indicating an important role of this phospholipid in cancer cell growth and motility in at least some types of neoplastic changes. [52][53][54] For the first time, we present the results of a study on the impact of LCE on PAF production. LCE significantly reduced PAF secretion by HUVECs stimulated with S. aureus peptidoglycan.…”

Platelet activating factor (PAF) and activity of its biosynthetic and catabolic enzymes in blood and leukocytes of male patients with newly diagnosed heart failure

“…In view of the fact that CD40 and sCD14 have been previously shown to induce or modulate PAF synthesis in cell lines [38,40,41], an upregulation of PAFbiosynthesis enzymes could be hypothesized. Moreover, CD40L is associated with expression of growth factors and cytokines [42], which can provide another mechanism of PAF synthesis modulation [43].…”

Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) as a therapeutic target to prevent retinal vasopermeability during diabetes

“…Elevated Lp-PLA 2 has been proposed as a predictive biomarker in stroke (10), atherosclerosis (11), and coronary heart disease (12). Macrophages and other proinflammatory cells are a primary source of Lp-PLA 2 in the systemic circulation (13), although endothelial cells also express this enzyme (14).…”