Abstract 17117: Conditional Loss of Pten in Developing Epicardium Increases the Number of Muscularized Coronary Arteries in Adult Mice.
Epicardial contribution to the coronary arteries is temporally limited during cardiogenesis. Adult epicardial cells, however, retain their ability to migrate and differentiate into vascular cell types. Pathways that stimulate epicardial and blood vessel development are required for coronary vessel formation and involve activation of the phosphoinositol-3-kinase (PI3K) signaling pathway in epicardial cells. Our hypothesis is that inhibition of the PI3K pathway by phosphatase and tensin homolog on chromosome 10 (PTEN) limits normal development of the coronary vascular system. We tested this by conditionally deleting PTEN in the epicardial lineage in mice. We used a transgenic Cre expression line: WT1 (Bac) Cre-EGFP. WT1Cre mice were crossed to a conditional (floxed) allele of PTEN. Heart sections were analyzed for muscularized arteries and capillaries using antibodies to PECAM and smooth muscle myosin. PTEN Flox/Flox; WT1Cre mice were viable and fertile. Hearts from these mice were phenotypically normal except that they appeared to have more coronary vessels. Quantification of PECAM positive capillaries revealed no differences between mutants and littermates. Quantification of muscularized coronary vessels in three week old mice revealed that mutants had an average of 100.4 (n=7) muscularized vessels per section and control littermates had and average of 60.7 (n= 9). This was statistically significant and represented a 60.5% increase. Mutant hearts had Oil Red O stained fat deposits in and around coronary vessels and at the ventricular apex. Fat deposits were most pronounced on the dorsal aspect of mutant hearts along the coronary sinus and were not observed in control littermates. No tumors were observed in mutant hearts as old as 12 weeks from birth. We conclude that conditional loss of PTEN in mouse epicardium and its derivatives increases coronary artery density, but does not affect the capillary bed. Since PTEN is a tumor suppressor, we worried that tumors would appear in the heart, but they did not. We speculate that pharmacologic interventions that target PTEN or its downstream effectors may be useful for stimulating coronary vascular growth in persons with heart attack or coronary artery disease.
- © 2010 by American Heart Association, Inc.