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Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography, is weak. In this study, we report an angiogenesis-independent effect of VEGF on ischemic skeletal muscle, ie, upregulation of myoglobin after VEGF treatment. Mice received intramuscular injection with adenoviral VEGF-A or either adenoviral LacZ or PBS as control, followed by surgical induction of acute hindlimb ischemia at day 3. At day 6, capillary density was increased in calf muscle of Ad.VEGF-treated versus control mice (P<0.01). However, angiographic score of collateral arteries was unchanged between Ad.VEGF-treated and control mice. More interestingly, an increase in myoglobin was observed in Ad.VEGF-treated mice. Active myoglobin was 1.5-fold increased in calf muscle of Ad.VEGF-treated mice (P< or =0.01). In addition, the number of myoglobin-stained myofibers was 2.6-fold increased in Ad.VEGF-treated mice (P=0.001). Furthermore, in ischemic muscle of 15 limb amputation patients, VEGF and myoglobin were coexpressed. Finally, in cultured C2C12 myotubes treated with rhVEGF, myoglobin mRNA was 2.8-fold raised as compared with PBS-treated cells (P=0.02). This effect could be blocked with the VEGF receptor tyrosine kinase inhibitor SU5416. In conclusion, we show that VEGF upregulates myoglobin in ischemic muscle both in vitro and in vivo. Increased myoglobin expression in VEGF-treated muscle implies an improved muscle oxygenation, which may, at least partly, explain observed clinical improvements in VEGF-treated patients, in the absence of improved vascularization.

Background and Purpose: Creatine kinase-MB (CK-MB) increases in some patients with stroke, with no clear evidence of an acute coronary syndrome. Its elevations have been suggested to represent a biological marker for stroke-related myocardial injury. Troponin T has superior sensitivity and specificity to CK-MB in revealing minor myocardial injury. Therefore, we studied troponin T levels after stroke to determine whether troponin T increases in parallel to CK-MB., Methods: We made daily measurements of CK-MB, myoglobin, total creatine kinase (total CK), and troponin T levels up to day 5 in 32 patients with large hemispheric infarction and with no history of coronary heart disease. The daily enzyme levels were compared with those of a control group of 22 patients with neurological diseases other than stroke., Results: Serum CK-MB, myoglobin, and total CK levels were elevated above the cutoff value in 11, 26, and 20 patients with stroke, respectively. These enzyme levels gradually increased within the first 3 days and declined afterward. Troponin T did not exceed the reference range in any patients. One patient had elevated myoglobin and 3 had elevated total CK in the control group. The difference between groups was significant for CK-MB, myoglobin, and total CK at various time points., Conclusions: Troponin T, a more specific biochemical marker of myocardial injury, does not increase after stroke. Normal troponin T along with elevated CK-MB signifies that CK-MB is not the biological marker for myocytolysis. CK-MB elevations in stroke patients are likely to be noncardiac in origin.