ABSTRACT
BACKGROUND: Placental growth factor (PlGF), a homolog of vascular endothelial growth factor, is reported to stimulate angiogenesis and arteriogenesis in pathological conditions. It was recently demonstrated that PlGF is rapidly produced in myocardial tissue during acute myocardial infarction (MI). However, the effects of exogenous PlGF administration on the healing process after MI are not fully understood. The purpose of the present study was to examine whether PlGF treatment has therapeutic potential in MI. METHODS AND RESULTS: Recombinant human PlGF (rhPlGF: 10 microg) was administered continuously for 3 days in a mouse model of acute MI. rhPlGF treatment significantly improved survival rate after MI and preserved cardiac function relative to control mice. The numbers of CD31-positive cells and alpha-smooth muscle actin-positive vessels in the infarct area were significantly increased in the rhPlGF group. Endothelial progenitor cells (Flk-1(+)Sca-1(+) cells) were mobilized by rhPlGF into the peripheral circulation. Furthermore, rhPlGF promoted the recruitment of GFP-labeled bone marrow cells to the infarct area, but only a few of those migrating cells differentiated into endothelial cells. CONCLUSIONS: Exogenous PlGF plays an important role in healing processes by improving cardiac function and stimulating angiogenesis following MI. It can be considered as a new therapeutic molecule.
Subject(s)
Angiogenesis Inducing Agents/administration & dosage , Coronary Vessels/drug effects , Myocardial Infarction/drug therapy , Neovascularization, Physiologic/drug effects , Pregnancy Proteins/administration & dosage , Actins/metabolism , Animals , Antigens, Ly/metabolism , Cell Differentiation/drug effects , Cell Movement/drug effects , Coronary Vessels/metabolism , Coronary Vessels/physiopathology , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Green Fluorescent Proteins/biosynthesis , Green Fluorescent Proteins/genetics , Humans , Infusion Pumps, Implantable , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Placenta Growth Factor , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Recombinant Proteins/administration & dosage , Stem Cells/drug effects , Stem Cells/metabolism , Time Factors , Vascular Endothelial Growth Factor Receptor-1/administration & dosage , Vascular Endothelial Growth Factor Receptor-2/metabolism , Ventricular Function, Left/drug effects , Ventricular Remodeling/drug effectsABSTRACT
OBJECTIVE: Percutaneous coronary intervention (PCI) is currently the most widely accepted treatment for acute myocardial infarction (AMI). It remains unclear, however, whether post-AMI conditions might exacerbate neointimal hyperplasia and restenosis following PCI. Given that both a medial smooth muscle cell lineage and a bone marrow (BM)-derived hematopoietic stem cell lineage are now thought to contribute to neointima formation, the primary aims of the present study were to determine whether AMI augments neointimal hyperplasia at sites of arterial injury, and whether BM-derived cells contribute to that process. METHODS AND RESULTS: We simultaneously generated models of AMI and arterial injury in the same mice, some of which had received BM transplantation. We found that AMI augments neointimal hyperplasia at sites of femoral artery injury by approximately 35% (P<0.05), but that while BM-derived cells contributed to neointimal hyperplasia, they did not contribute to the AMI-related augmentation. Expression of interleukin (IL)-6 mRNA was approximately 7-fold higher in the neointimas of mice subjected to both AMI and arterial injury than in those of mice subjected to arterial injury alone. In addition, we observed increased synthesis of tumor necrosis factor (TNF)-alpha within infarcted hearts and TNF-alpha receptor type 1 (TNFR1) within injured arteries. Chronic treatment with pentoxifylline, which mainly inhibits TNF-alpha synthesis, reduced levels of circulating TNF-alpha and attenuated neointimal hyperplasia after AMI. CONCLUSIONS: Conditions after AMI could exacerbate postangioplasty restenosis, not by increasing mobilization of BM-derived cells, but by stimulating signaling via TNF-alpha, TNFR1 and IL-6.
Subject(s)
Femoral Artery/injuries , Femoral Artery/pathology , Myocardial Infarction/complications , Vasculitis/etiology , Vasculitis/pathology , Animals , Bone Marrow Cells/pathology , Cytokines/metabolism , Femoral Artery/drug effects , Femoral Artery/metabolism , Hyperplasia , Inflammation Mediators/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myocardial Infarction/metabolism , Myocardium/metabolism , Pertussis Toxin/pharmacology , Receptors, Tumor Necrosis Factor, Type I/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , Tunica Intima/pathology , Wounds and Injuries/metabolism , Wounds and Injuries/pathologyABSTRACT
OBJECTIVES: Our aim was to investigate cardiac expression of placental growth factor (PlGF) and its clinical significance in patients with acute myocardial infarction (AMI). BACKGROUND: Placental growth factor is known to stimulate wound healing by activating mononuclear cells and inducing angiogenesis. The clinical significance of PlGF in AMI is not yet known. METHODS: Fifty-five AMI patients and 43 control subjects participated in the study. Peripheral blood sampling was performed on days 1, 3, and 7 after AMI. Blood was also sampled from the coronary artery (CAos) and the coronary sinus (CS), before and after acute coronary recanalization. Cardiac expression of PlGF was analyzed in a mouse AMI model. RESULTS: In AMI patients, peripheral plasma PlGF levels on day 3 were significantly higher than in control subjects. Plasma PlGF levels just after recanalization were significantly higher in the CS than the CAos, which indicates cardiac production and release of PlGF. Peripheral plasma levels of PlGF on day 3 were negatively correlated with the acute phase left ventricular ejection fraction (LVEF), positively correlated with both acute phase peak peripheral monocyte counts and chronic phase changes in LVEF. Placental growth factor messenger ribonucleic acid expression was 26.6-fold greater in a mouse AMI model than in sham-operated mice, and PlGF was expressed mainly in endothelial cells within the infarct region. CONCLUSIONS: Placental growth factor is rapidly produced in infarct myocardium, especially by endothelial cells during the acute phase of myocardial infarction. Placental growth factor might be over-expressed to compensate the acute ischemic damage, and appears to then act to improve LVEF during the chronic phase.
