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Coronary artery disease (CAD) is the leading cause of mortality in diabetic patients. Because of the diffuse nature of their disease, diabetic patients may be at risk for incomplete revascularization, highlighting a potential role for proangiogenic therapy in this group. This study investigates molecular mechanisms of angiogenesis in diabetic patients. Myocardial tissue was harvested from patients undergoing coronary artery bypass grafting [nondiabetic (ND) 11, type 2 diabetic (DM) 10]. Expression of angiostatin, endostatin, their precursors (plasminogen and collagen XVIII, respectively), enzymes leading to their production [matrix metalloprotease (MMP)-2 and -9, cathepsin L], and an inhibitor of MMPs (tissue inhibitor of metalloproteinase) was assessed with Western blotting. MMP activity was assessed. Coronary collateralization was graded by Rentrop scoring of angiograms. Plasminogen and collagen XVIII expression were similar between groups. Angiostatin expression trended to increase 1.24-fold (P = 0.07), and endostatin expression increased 2.02-fold in DM patients relative to ND (P = 0.02). MMP-9 expression was no different between groups, whereas MMP-2 expression decreased 1.8-fold in diabetics (P = 0.003). MMP-2 and -9 activity decreased 1.33-fold (P = 0.03) and 1.57-fold (P = 0.04), respectively, in diabetic patients. Cathepsin L expression was 1.38-fold higher in diabetic patients (P = 0.02). Coronary collateralization scores were ND 2.1 [+ or -] 0.37 vs. DM 1.0 [+ or -] 0.4 (P = 0.05). Myocardial endostatin expression correlated strongly with the percentage of hemoglobin [A.sub.1c] (r = 0.742, P = 0.0001). Myocardial expression of angiostatin and endostatin demonstrated significant negative linear correlations with coronary collateralization (angiostatin r = -0.531, P = 0.035, endostatin r = -0.794, P = 0.0002). Diabetic patients with CAD exhibit increased levels of the antiangiogenie proteins angiostatin and endostatin and differential regulation of the enzymes governing their production relative to ND patients. Myocardial levels of these proteins show significant correlation to coronary collateralization. These findings offer potential new therapeutic targets for enhancing proangiogenic therapy and insight into the angiogenic impairments seen in diabetes. matrix metalloprotease; tissue inhibitor of metalloprotease

The mechanism of exercise-induced benefit and angiogenesis in ischemic heart disease remains poorly defined. This study was designed to investigate the effects of exercise training on the expression of angiogenic factors and angiogenesis in the infarcted myocardium [myocarial infaction (MI)]. Sixty-three male FVB mice were used for study and were divided into subgroups to test the response to exercise: the time-dependent expression of angiogenic factors to exercise training in normal (group 1; n = 12) and infarcted myocardium (group 2; n = 15) and the exerciseinduced angiogenic response in normal and infarcted myocardium (group 3; n = 20) as well as the impact of exercise preconditioning on infarcted myocardium (group 4; n = 26). Exercise training consisted of daily treadmill exercise for 1 h for 3 days. Expression of VEGF and its receptors Flt-1 and Flk-1 was upregulated by exercise training in mice with MI. Exercise-induced VEGF expression in the MI group was higher than that in the sham (control) group. Cell proliferation assessment showed a significantly higher (P < 0.05) number of bromodeoxyuridine-positive cells in post-MI mice in the exercise group as opposed to post-MI mice in the sedentary group. 2,3,5-Triphenyltetrazolium chloride staining revealed a profound difference in the size of MI (18.25 [+ or -] 2.93%) in the exercise group versus the sedentary group (29.26 [+ or -] 7.64%, P = 0.02). Moreover, exercise preconditioning before MI promoted VEGF expression at both mRNA and protein levels. In conclusion, activation of VEGF and its receptors occurs in the infarcted mice heart in response to exercise, which results in decreased infarct size and improved angiogenesis. exercise; angiogenesis; ischemic heart disease; vascular endothelial growth factor

Despite promising preclinical results, transient single-factor-based therapeutic angiogenesis has shown no definitive benefits in clinical trials. The use of skin-derived microorgans (SMOs), capable of sustained expression of angiogenic factors and sustained viability with their cellular and extracellular elements, constitutes an attractive alternative. We sought to evaluate the efficacy of SMO implantation in a porcine model of chronic myocardial ischemia. Eighteen pigs underwent placement of an ameroid constrictor on the proximal circumflex artery. Three weeks later, split-thickness skin biopsies were harvested and pigs were randomized to lateral wall implantation of either 8 or 16 SMOs or blank injections. The procedure was safe and resulted in no adverse events. Three weeks after treatment, SMO implantation resulted in significant improvement of lateral wall perfusion during pacing, assessed by isotope-labeled microspheres [post- vs. pretreatment ratios of lateral/anterior wall blood flow were 1.31 [+ or -] 0.09 (SMOs) and 1.04 [+ or -] 0.06 (controls); P = 0.03]. No significant difference in angiographic scores was observed. Microvascular relaxation in response to VEGF was impaired in the ischemic territory of the control group but returned to normal after SMO implantation, indicating restoration of endothelial function. Molecular studies showed significant increases in VEGF and CD31 expression in the ischemic area of treated animals. Morphometric analysis showed increased neovascularization with SMO treatment. Autotransplantation of SMOs constitutes a novel approach for safe and effective therapeutic angiogenesis with improvement in perfusion, normalization of microvascular reactivity, and increased expression of VEGF and CD31. growth factors; myocardial ischemia

Enhanced external counterpulsation (EECP) is an effective noninvasive treatment of coronary artery disease. Its mechanism of action remains unknown. An acute coronary occlusion dog model was created to explore the angiogenic effect of EECP. After coronary occlusion, 12 dogs were randomly assigned to either EECP (n = 6) or control (n = 6). Immunohistochemical studies of [alpha]-actin and von Willebrand factor (vWF) were used to detect newly developed microvessels. Systemic and local vascular endothelial growth factor (VEGF) were identified by ELISA and reverse transcriptase PCR analysis. There was a significant increase in the density of microvessels per squared millimeter in the infarcted regions of the EECP group compared with the control group (vWF, 15.2 [+ or -] 6.3 vs. 4.9 [+ or -] 2.1, P < 0.05; [alpha]-actin, 11.8 [+ or -] 5.3 vs. 3.4 [+ or -] 1.2, P < 0.05). The positive-stained area per squared micrometer also increased significantly ([alpha]-actin, 6.6 x [10.sup.3] [+ or -] 2.9 x [10.sup.3] [micro][m.sup.2] vs. 0.6 x [10.sup.3] [+ or -] 0.5 x [10.sup.3] [micro][m.sup.2], P < 0.05; vWF, 5.7 x [10.sup.3] [+ or -] 1.9 x [10.sup.3] [micro][m.sup.2] vs. 1.7 x [10.sup.3] [+ or -] 1.4 x [10.sup.3] [micro][m.sup.2], P < 0.05). Immunohistochemical staining and reverse transcriptase PCR analysis documented a significant increase in VEGF expression. These factors associated with angiogenesis corresponded to improved myocardial perfusion by [sup.99m]Tc-sestamibi single-photon emission computed tomography. Angiogenesis may be a mechanism of action for the improved myocardial perfusion demonstrated after EECP therapy. angiogenesis; collateral circulation; growth factors; infarction; ventricular function

There is increasing evidence that cyclooxygenase (COX)-2 possess both angiogenic and cardioprotective properties. We examined the effects of hypoxic cardiac myocytes (H9c2 cells) on COX-2 expression in human umbilical vein endothelial cells (HUVECs) to determine the pathway involved in COX-2 regulation. The medium from hypoxic ( cyclooxygenase-2; vascular endothelial growth factor; cardiac myocytes

An experiment was performed to investigate the hemodynamic effects of intracoronary vascular endothelial growth factor (VEGF) administration and the function of nitric oxide (NO) in VEGF-induced vasodilation in vivo. Intracoronary administration of VEGF was linked to alterations in coronary blood flow and systemic hemodynamics. Vasodilation effects of VEGF delivery were affected by the presence of NO. Different results from the in vivo and in vitro studies of VEGF administration and absence of changes in the heart rates were also observed.

Dr Laham is an instructor in medicine at Harvard Medical School and Beth Israel Hospital, Boston. Dr Josephson is professor of medicine at Harvard Medical School and director of the [...]