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Assessing Therapeutic Angiogenesis in a Murine Model of Hindlimb Ischemia
Published on: June 8, 2019
Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in
Munir Boodhwani1, Neel R Sodha, Shigetoshi Mieno
1Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, MA 02215, USA.
Insights
Diabetic patients have impaired heart blood vessel formation during ischemia. This study shows diabetes reduces pro-angiogenic factors and increases anti-angiogenic factors, offering new therapeutic targets.
Area of Science:
- Cardiovascular Research
- Metabolic Disease Research
- Angiogenesis Studies
Background:
- Ischemic heart disease is a leading cause of death in diabetic patients.
- Diabetics exhibit diminished collateral vessel formation after myocardial ischemia.
- Understanding diabetes' impact on angiogenesis is crucial for developing effective therapies.
Purpose of the Study:
- Establish a large animal model for diabetes and chronic myocardial ischemia.
- Assess diabetes' effects on the heart's angiogenic response.
- Investigate the underlying molecular pathways involved in impaired angiogenesis.
Main Methods:
- Induced diabetes in Yucatan miniswine using alloxan.
- Created chronic myocardial ischemia via ameroid constrictor placement.
- Evaluated myocardial perfusion, cardiac function, endothelial cell density, and angiogenic mediator expression.
Main Results:
- Diabetic swine showed impaired collateral-dependent perfusion and left ventricular function.
- Reduced endothelial cell density was observed in diabetic animals.
- Key pro-angiogenic factors (VEGF, Ang-1, Tie-2) were decreased, while anti-angiogenic factors (angiostatin, endostatin) were elevated.
Conclusions:
- Diabetes significantly impairs the heart's ability to form new blood vessels in response to chronic ischemia.
- Specific pro- and anti-angiogenic mediators identified present potential therapeutic targets.
- Modulating these mediators could improve angiogenic responses in diabetic patients.
Background:
Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved.
Methods And Results:
Diabetes was induced in male Yucatan miniswine using a pancreatic beta-cell specific toxin, alloxan (150 mg/kg; n=8). Age-matched swine served as controls (n=8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173+/-14 versus 234+/-23 cells/hpf, P=0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4+/-0.9-fold increase, P<0.001), and endostatin (2.9+/-0.4-fold increase, P=0.03) were significantly elevated in the diabetic myocardium.
Conclusions:
Diabetes results in a profound impairment in the myocardial angiogenic response to chronic ischemia. Pro- and antiangiogenic mediators identified in this study offer novel targets for the modulation of the angiogenic response in diabetes.
