A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function

Giordano, Frank J.; Gerber, Hans‐Peter; Williams, Simon‐Peter; VanBruggen, N; Bunting, Stuart; Ruiz‐Lozano, Pilar; Gu, Yusu; Nath, Anjali K.; Huang, Yan; Hickey, Reed; Dalton, Nancy D.; Peterson, Kirk L.; Ross, John; Chien, Kenneth R.; Ferrara, Napoleone

doi:10.1073/pnas.091415198

Cited by 340 publications

(286 citation statements)

References 36 publications

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“…5) in vitro. Both of these growth factors are known to be present within the myocardium of the developing heart and to be necessary for proper heart development (Dickson et al 1993;Boyer et al 1999;Tomanek et al 1999;Giordano et al 2001;Camenisch et al 2002). From these results, we conclude that our in vitro embryonic myocyte cultures recapitulate cardiac gene expression and growth factor production related to proliferative potential and myocyte maintenance.…”

Section: Resultssupporting

confidence: 58%

An improved protocol for the isolation and cultivation of embryonic mouse myocytes

2009

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In vitro cultures of cardiomyocytes have proven to be a useful tool for toxicological, pharmacological, and developmental studies, as well as for the study of the cellular and molecular mechanisms responsible for proper myocyte function. One deficient area of research is that of myocyte proliferation. Cardiomyocyte proliferation dramatically diminishes soon after birth and has a very limited occurrence within the adult heart, thus limiting the use of adult cells for proliferation studies. An improved understanding of the requirements for myocyte proliferation will allow for the development of better approaches to repair damaged heart tissue. Here, we provide a protocol for the reliable isolation of embryonic mouse myocytes. These myocytes behave similarly to those in vivo, including their ability to proliferate, providing an ideal system for the study of cardiomyocyte proliferation.

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Section: Resultssupporting

confidence: 58%

An improved protocol for the isolation and cultivation of embryonic mouse myocytes

2009

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“…Anticipating microvascular alterations following VEGF disruption, and extending the results reported with the initial characterization of the cardiomyocyte-specific VEGF knockout mice (13), the capillary density was quantitated in the hearts and other tissues of knockout and control animals. A reduced vessel density might plausibly lead to chronic hypoxic ischemia with corresponding evidence of fibrosis, necrosis, or changes in myofibrillar morphology (17).…”

mentioning

confidence: 89%

“…The techniques used to generate this mouse line have been described previously (13). Briefly, one parent strain was heterozygous for Cre recombinase under the myosin light chain 2v promoter, which directed expression to the ventricular myocytes beginning around day E12.5.…”

Section: Cardiomyocyte-specific Vegf Knockoutmentioning

confidence: 99%

“…This model may be of some value in designing and evaluating angiogenic therapies (11), and in understanding the pathophysiology of chronic ischemic conditions associated with coronary artery disease (12). The generation and preliminary phenotypic characterization of this mouse model has recently been described (13). Briefly, the Cre/lox system (14) was employed to generate a targeted knockout of vascular endothelial growth factor A (VEGF A) specific to the ventricular cardiomyocytes.…”

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confidence: 99%

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Dobutamine stress cine‐MRI of cardiac function in the hearts of adult cardiomyocyte‐specific VEGF knockout mice

Williams¹,

Gerber²,

Giordano³

et al. 2001

Magnetic Resonance Imaging

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A mouse model of non-necrotic vascular deficiency in the adult heart was studied using cine-magnetic resonance imaging (MRI) and other techniques. The mice lacked cardiomyocyte-derived vascular endothelial growth factor (VEGF) following a targeted knockout in the ventricular cardiomyocytes. Quantitative endothelial labeling showed that the capillary density was significantly reduced in the hearts of knockout mice. Gene expression patterns suggested that they were hypoxic. Semiautomated MR image analysis was employed to obtain both global and regional measurements of left ventricular function at 10 or more time points through the cardiac cycle. MRI measurements showed a marked reduction in ejection fraction both at rest and under low-and high-dose dobutamine stress. Regional wall thickness, thickening, and displacement were all attenuated in the knockout mice. A prolonged high-dose dobutamine challenge was monitored by MRI. A maximal response was sustained for 90 minutes, suggesting that it did not depend on endogenous glycogen stores. J. Index terms: VEGF; cine; dobutamine; mouse; heart THE RECENT PROLIFERATION of murine models of human heart disease has been remarkable (1) and is likely to continue. Although MRI has been elegantly applied by several groups to studies of the mouse heart (e.g., Refs. 2-5), it remains concentrated in relatively few centers. Cardiac MRI of the mouse, unlike of the rat (6), is not widespread in the pharmaceutical research setting, but that seems likely to change as the advantages of murine models increasingly outweigh their disadvantages. There are important biological differences between the hearts of different mammals, such as in calcium handling (7) and vascular anatomy (8), yet many of the perceived disadvantages of using mice as opposed to larger animal species are essentially technical in nature. This has spurred great efforts in adapting radiological, surgical, and physiological techniques to the temporal and spatial scale of the mouse heart (9,10).This paper describes MRI of the left ventricle (LV) under resting and stressed conditions in a mouse model of a non-necrotic vascular deficiency in the adult heart. This model may be of some value in designing and evaluating angiogenic therapies (11), and in understanding the pathophysiology of chronic ischemic conditions associated with coronary artery disease (12). The generation and preliminary phenotypic characterization of this mouse model has recently been described (13). Briefly, the Cre/lox system (14) was employed to generate a targeted knockout of vascular endothelial growth factor A (VEGF A) specific to the ventricular cardiomyocytes. VEGF A is a potent cytokine and mitogen involved in the formation and maintenance of blood vessels (15). Attempts to generate VEGF A knockouts by the more common germ-line strategies were confounded by the highly unusual embryonic lethality seen in VEGF A heterozygotes (16).The effect of the gene knockout was monitored directly (changes in VEGF A mRNA) and indirectly. Anticipating microvasc...

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“…8,9 Furthermore, myocyte-secreted VEGF, acting via autocrine and paracrine pathways, has been shown to be critically important to the maintenance of normal ventricular structure and function. 10 It is thought that local decreases in myocyte-secreted tissue VEGF contribute to as yet unspecified mechanisms of ischemic heart failure, especially in diabetes. 11 We have demonstrated earlier the ability of TERPLEXmediated plasmid VEGF gene therapy to ameliorate the detrimental effects of coronary occlusion on left ventricular function and to promote functional recovery following myocardial infarction.…”

Section: Introductionmentioning

confidence: 99%

Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct

et al. 2008

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A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function

Cited by 340 publications

References 36 publications

An improved protocol for the isolation and cultivation of embryonic mouse myocytes

An improved protocol for the isolation and cultivation of embryonic mouse myocytes

Dobutamine stress cine‐MRI of cardiac function in the hearts of adult cardiomyocyte‐specific VEGF knockout mice

Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct

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