Abstract-Vascular endothelial growth factor (VEGF)-B is poorly angiogenic but prominently expressed in metabolically highly active tissues, including the heart. We produced mice expressing a cardiac-specific VEGF-B transgene via the ␣-myosin heavy chain promoter. Surprisingly, the hearts of the VEGF-B transgenic mice showed concentric cardiac hypertrophy without significant changes in heart function. The cardiac hypertrophy was attributable to an increased size of the cardiomyocytes. Blood capillary size was increased, whereas the number of blood vessels per cell nucleus remained unchanged. Despite the cardiac hypertrophy, the transgenic mice had lower heart rate and blood pressure than their littermates, and they responded similarly to angiotensin II-induced hypertension, confirming that the hypertrophy does not compromise heart function. Interestingly, the isolated transgenic hearts had less cardiomyocyte damage after ischemia. Significantly increased ceramide and decreased triglyceride levels were found in the transgenic hearts. This was associated with structural changes and eventual lysis of mitochondria, resulting in accumulation of intracellular vacuoles in cardiomyocytes and increased death of the transgenic mice, apparently because of mitochondrial lipotoxicity in the heart. These results suggest that VEGF-B regulates lipid metabolism, an unexpected function for an angiogenic growth factor. Key Words: VEGF-B Ⅲ cardiac hypertrophy Ⅲ cardiac metabolism Ⅲ fatty acids Ⅲ mitochondria M embers of the vascular endothelial growth factor (VEGF) family, currently comprising 5 mammalian proteins, are major regulators of blood and lymphatic vessel development and growth. VEGF is essential for vasculogenesis and angiogenesis, whereas VEGF-C is necessary for lymphangiogenesis. Although not required for embryonic development, placenta growth factor and VEGF-D are likely to play more subtle roles in the control of angiogenesis and lymphangiogenesis, or function under pathological conditions. 1,2 VEGF-B exists as 2 isoforms generated by alternative splicing. VEGF-B 167 has a heparin-binding carboxyl terminus, whereas VEGF-B 186 contains a hydrophobic carboxyl terminus, is O-glycosylated, and proteolytically processed. 3 Both isoforms bind to VEGF receptor (VEGFR)-1 and neuropilin-1 but not to the major mitogenic endothelial cell receptors VEGFR-2 or VEGFR-3. 4,5 VEGF-B has a wide tissue distribution, being most abundant in the myocardium, skeletal and vascular smooth muscle, as well as in brown adipose tissue. 6 Mice lacking VEGF-B are viable and fertile and display only a mild phenotype in the heart. This is manifested as an atrial conduction abnormality characterized by a prolonged PQ interval in 1 strain (C57Bl background), 7 or as a smaller heart size with impaired recovery after myocardial ischemia in another (129/SvJ or 129/SvJϫC57Bl/6J background). 8 Furthermore, VEGF-B has also been implicated in pathological vascular changes in inflammatory arthritis 9 and in protecting the brain from ischemic injury. 10 H...

Longitudinal relaxation time in the rotating frame (T1ρ) was measured using continuous wave irradiation in normal and infarcted mouse myocardium in vivo. Significant increase in T1ρ was found after 7 days of infarction when compared with reference myocardium or in myocardium before infarction. Cine MRI and histology were performed to verify the severity of infarction. The time course of T1ρ in the infarct fits better with granulation and scar tissue formation than necrosis and edema. The results of the study show that T1ρ could potentially be a noninvasive quantitative marker for tissue remodeling after ischemic damage.

AdVEGF-B(186) and AdVEGF-E are equally potent in inducing therapeutic angiogenesis in mouse myocardium and produce less side effects than AdVEGF-A(165).

Mechanisms of the transition from compensatory hypertrophy to heart failure are poorly understood and the roles of vascular endothelial growth factors (VEGFs) in this process have not been fully clarified. We determined the expression profile of VEGFs and relevant receptors during the progression of left ventricular hypertrophy (LVH). C57BL mice were exposed to transversal aortic constriction (TAC) and the outcome was studied at different time points (1 day, 2, 4, and 10 weeks). A clear compensatory phase (2 weeks after TAC) was seen with following heart failure (4 weeks after TAC). Interestingly, VEGF-C and VEGF-D as well as VEGF receptor-3 (VEGFR-3) were upregulated in the compensatory hypertrophy and VEGF-B was downregulated in the heart failure. After treatment with adeno-associated virus serotype 9 (AAV9)-VEGF-B(186) gene therapy in the compensatory phase for 4 weeks the function of the heart was preserved due to angiogenesis, inhibition of apoptosis, and promotion of cardiomyocyte proliferation. Also, the genetic programming towards fetal gene expression, a known phenomenon in heart failure, was partly reversed in AAV9-VEGF-B(186)-treated mice. We conclude that VEGF-C and VEGF-D are associated with the compensatory LVH and that AAV9-VEGF-B(186) gene transfer can rescue the function of the failing heart and postpone the transition towards heart failure.