thromboxane-a2 and Hyperplasia

Pulmonary vascular disease, a serious complication of many congenital heart lesions, has three major components: increased muscularity of small pulmonary arteries; intimal hyperplasia, scarring and thrombosis; and reduced numbers of intraacinar arteries. The muscularity is due to increased stress on the vessel wall, and is reversible. The intimal changes may be due to endothelial damage, causing an imbalance between prostacyclin and thromboxane A2 production and leading to local platelet aggregation. This, in turn, may stimulate migration and division of myointimal cells, which thicken the intima and lead to scarring and thrombosis. Extensive intimal changes are probably irreversible, but the possibility of preventing them by use of agents that inhibit platelet aggregation needs to be considered. The mechanism of a decrease in numbers of intraacinar arteries is unexplained. The potential for growth of new vessels after corrective surgery of the cardiac defect is an important factor in restoring pulmonary vascular resistance to normal. Available evidence suggests that this growth potential is reduced after 2 years of age and argues for early surgical relief of pulmonary vascular stresses.

Topics: Animals; Child; Child, Preschool; Dogs; Ductus Arteriosus, Patent; Epoprostenol; Female; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hyperplasia; Infant; Lung Diseases; Muscle, Smooth; Platelet Aggregation; Pregnancy; Pulmonary Artery; Tetralogy of Fallot; Thromboxane A2; Transposition of Great Vessels; Vascular Diseases; Vascular Resistance

Vascular smooth muscle cells (VSMC) undergo hypertrophy when exposed to thromboxane A2 and hyperplasia when exposed to phorbol 12-myristate 13-acetate (PMA) or platelet-derived growth factor (PDGF). Each of these three agonists stimulate rapid tyrosine phosphorylation of numerous VSMC proteins. The current studies were undertaken to identify proteins that are specifically tyrosine phosphorylated in one or the other growth response. All three agonists increased the phosphotyrosine content of multiple proteins. In Western analysis of phosphotyrosine immunoprecipitates, the hyperplastic agents PDGF and PMA increased tyrosine phosphorylation of phospholipase C-gamma 1 (PLC-gamma 1), GTPase-activating protein (GAP), and phosphatidylinositol-3-kinase (PI-3-kinase), while the hypertrophic agonist thromboxane failed to tyrosine-phosphorylate either of these three substrates. Tyrosine kinase inhibition with herbimycin A (5 microM) prevented agonist-stimulated tyrosine phosphorylation of PLC-gamma 1, GAP, and PI-3-kinase. In growth studies, herbimycin A inhibited PMA- and PDGF-induced hyperplasia but not thromboxane-stimulated hypertrophy. These results indicate that tyrosine phosphorylation of PLC-gamma 1, GAP, and PI-3-kinase are specific responses for VSMC hyperplasia but not thromboxane-stimulated hypertrophy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cells, Cultured; Hyperplasia; Hypertrophy; Muscle, Smooth, Vascular; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Platelet-Derived Growth Factor; Prostaglandin Endoperoxides, Synthetic; Protein-Tyrosine Kinases; Rats; Tetradecanoylphorbol Acetate; Thromboxane A2; Type C Phospholipases; Tyrosine

Topics: Animals; Dose-Response Relationship, Drug; Epoprostenol; Hyperplasia; Juxtaglomerular Apparatus; Kidney Diseases; Kidney Tubules; Rats; Rats, Inbred Strains; Tacrolimus; Thromboxane A2; Time Factors

This study evaluated the efficacy of a prostacyclin analog, iloprost, and a thromboxane A2 receptor antagonist, daltroban, as inhibitors of experimental intimal hyperplasia. The vascular injury model used is based on an endothelial injury induced by a brief infusion of air into an isolated segment of the common carotid artery in the rat. Iloprost and daltroban were administered by continuous IV infusion for two weeks. The infusion rates were 0.1 micrograms/kg/min for iloprost and 0.1 mg/kg/hr for daltroban; these dosing rates are associated with significant alterations in eicosanoid-related pharmacologic effects. The animals were sacrificed at two weeks and the carotid arteries fixed in situ for light microscopy. The myointimal thickening was measured as the intima to media area (I/M) ratio. The control animals developed marked intimal thickening, with an I/M ratio of 0.76 +/- 0.12 (mean +/- SEM; N = 7). There was no inhibition of intimal hyperplasia (P greater than 0.05) after either iloprost (I/M ratio: 1.04 +/- 0.13; N = 8) or daltroban (I/M ratio: 0.70 +/- 0.04; N = 6). It is concluded that neither of these two modulators of eicosanoid activity, iloprost and daltroban, inhibit intimal hyperplasia following experimental endothelial injury.

Topics: Animals; Carotid Arteries; Carotid Artery Injuries; Endothelium, Vascular; Hyperplasia; Iloprost; In Vitro Techniques; Infusions, Intravenous; Male; Phenylacetates; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2