Myofibroblast and endothelial cell proliferation during murine myocardial infarct repair.
Granulation tissue formation is a critical step in infarct repair, however, the kinetics of cell replication and the molecules that regulate this process are poorly understood. In uninjured mouse hearts and at 2 days post-infarction, very little DNA synthesis (measured by incorporation of a BrdU pulse) was detected in any cell type. Four days after permanent coronary occlusion, the rates of myofibroblast (smooth muscle alpha-actin and BrdU double-positive) and endothelial cell (CD31 and BrdU double-positive) proliferation were 15.4 +/- 1.1% and 2.9 +/- 0.5%, respectively. Most proliferating cells were located at the interface of the infarct and viable tissue. By 1 week, fibroblast and endothelial cell proliferation declined to 4.1 +/- 0.6% and 0.7 +/- 0.1%, respectively. In the 2-week infarct, the remaining necrosis had been phagocytosed, and fibroblast and endothelial cell proliferation were <0.5%. Although leukocytes were abundant throughout infarct repair, no significant proliferation was detected at any time in cells expressing CD45 or mac-3. Infarct size at 4 days was 38 +/- 5% of the left ventricle and contracted to 20 +/- 4% by 4 weeks. After 4 days, the chamber dilated to four times that of the control hearts and remained so for the duration of the time course. The vascular density (per mm(2)) declined from 3643 +/- 82 in control hearts to 2716 +/- 197 at 1 week and 1010 +/- 47 at 4 weeks post-myocardial infarction (MI). The average percent area occupied by vessels did not change significantly between the groups but the area/vessel ( micro m(2)) increased from 14.1 +/- 0.3 in control hearts to 16.9 +/- 1.9 at 1 week and 38.7 +/- 7.9 at 4 weeks post-MI. These data indicate that mitogens for fibroblasts and endothelial cells peak within 4 days of infarction in the mouse heart. This provides the basis for identifying the responsible molecules and developing strategies to alter wound repair and improve cardiac function.
Virag
Jitka Ismail
JI
Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Murry
Charles E
CE
D000818:Animals; D002455:Cell Division; D002908:Chronic Disease; D042783:Endothelial Cells / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology*; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000473:pathology*; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology*; D013997:Time Factors; D014945:Wound Healing