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Time course of mitosis and collateral growth following coronary microembolization in the porcine heart
R Zimmermann1, M Arras, C Ullmann
1Max Planck Institute for Physiological and Clinical Research, Department of Experimental Cardiology, Benekestrasse 2, D-61231 Bad Nauheim, Germany. rzimmer@kerckhoff.mpg.de
Insights
Coronary microembolization in pigs stimulates rapid collateral vessel growth (angiogenesis) within days. Histone H3 and PCNA/cyclin markers reliably indicate this increased vascular proliferation in ischemic heart tissue.
Area of Science:
- Cardiovascular Research
- Vascular Biology
- Myocardial Ischemia
Background:
- Angiogenesis, the growth of new blood vessels, is crucial for recovery in ischemic heart tissue.
- Endothelial cell mitosis is a fundamental process driving angiogenesis.
Purpose of the Study:
- To investigate the temporal dynamics of endothelial cell mitosis as a marker for angiogenesis in a porcine model of coronary microembolization.
- To establish the time course of vascular growth following induced myocardial ischemia.
Main Methods:
- Induction of myocardial ischemia using 25-microm microspheres in the left circumflex artery of pigs.
- Tissue analysis at 24, 72, and 168 hours post-microembolization using histone H3 in-situ hybridization, PCNA/cyclin immunohistochemistry, and electron microscopy.
- Quantitative comparison of blood vessel density between ischemic and non-ischemic myocardium.
Main Results:
- Increased proliferation of endothelial cells, marked by histone H3 and PCNA/cyclin positivity, was observed as early as 24 hours post-microembolization in necrotic foci.
- Significant increases in blood vessel numbers were detected in ischemic myocardium at 72 and 168 hours compared to controls.
- Cellular proliferation rates returned to baseline levels by 168 hours, while enhanced capillary growth persisted.
Conclusions:
- Coronary microembolization triggers a significant proliferative response and enhanced capillary growth in porcine myocardium within the first week.
- Histone H3 in-situ hybridization and PCNA/cyclin immunohistochemistry are effective markers for assessing proliferation and vascular growth in non-cancerous tissues.
- This study provides a reliable timeline for angiogenesis following acute myocardial ischemia in a preclinical model.
Abstract:
In ischaemic porcine myocardium, the growth of collateral vessels by angiogenesis is observed in clusters in the vicinity of focal necroses. Because mitosis of endothelial cells is a prerequisite for angiogenesis, the purpose of this study has been to evaluate the time course of mitosis as an indicator of vascular growth in a porcine model of coronary microembolization. Ischaemia was induced by injection of 25-microm microspheres in the left circumflex artery, followed by tissue collection from non-ischaemic and ischaemic areas of the same heart after 24, 72 or 168 h microembolization. Tissue was studied by histone H3 in-situ hybridization, PCNA/cyclin immunohistochemistry and electron microscopy. The number of blood vessels in ischaemic myocardium was compared with that in normal control tissue. Capillary growth started as early as 24 h after microembolization, as indicated by increasing numbers of proliferating, histone H3- and PCNA/cyclin-positive cells in the necrotic inflammatory foci of the ischaemic area. At 72 h and 168 h, the number of blood vessels was significantly higher in ischaemic than in normal myocardium, whereas at 168 h, mitosis of cells was, as in normal myocardium, a rare event. Coronary microembolization of porcine myocardium thus leads to an increased cellular proliferation rate between 24 h and less than 7 days after the onset of microembolization, followed by enhanced capillary growth. In-situ hybridization with histone H3 and PCNA/cyclin immunohistochemistry seem to be reliable markers for proliferation and vascular growth in non-cancerogenic tissue.
