The effects of VEGF-R1 and VEGF-R2 ligands on angiogenic responses and left ventricular function in mice

Huusko, Jenni; Merentie, Mari; Dijkstra, Marike H.; Ryhänen, Minttu-Maria; Karvinen, Henna; Rissanen, Tuomas T.; Vanwildemeersch, Maarten; Hedman, Marja; Lipponen, Jukka A.; Heinonen, Suvi; Eriksson, Ulf; Shibuya, Masabumi; Ylä‐Herttuala, Seppo

doi:10.1093/cvr/cvp382

Cited by 47 publications

(50 citation statements)

References 28 publications

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“…The experimental animal model of acute coronary artery ligation was developed in 10-wk-old male C57BL/6J mice (Harlan) as previously described (23). Immediately after coronary artery ligation, 1 ϫ 10 10 Ad-shPDE5a particles were injected at four or five sites per mouse heart along the anterior and posterior LV wall (17). Ad-Null or DMEM was injected in the same manner in the control animals.…”

Section: Methodsmentioning

confidence: 99%

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

Haider

Wang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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short hairpin rna therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol 302: H2112-H2121, 2012. First published March 23, 2012 doi:10.1152 doi:10. /ajpheart.00339.2011 showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction.

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Section: Methodsmentioning

confidence: 99%

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

Haider

Wang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…in ischemic heart disease, and VEGF-B has been suggested as a candidate for the therapy of dilated cardiomyopathy (11,(13)(14)(15)(16). Interestingly, exogenous VEGF-B maintained mitochondrial respiratory complex 1 function after ischemia/reperfusion injury and protected the heart from ischemic damage (11).…”

Section: Significancementioning

confidence: 99%

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Räsänen

Degerman

Nissinen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

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Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients.

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“…Increased coronary growth was also detected in cardiac-specific VEGF-B transgenic rats but not mice (14,62). The cardiac hypertrophy in the VEGF-B transgenic mice was suggested to be dependent on Vegfr1 expression by cardiomyocytes, although this is in contrast to previous reports (35,56,121). Potentially, the cardiac hypertrophy could involve paracrine signaling between ECs and cardiomyocytes by additional ligands (14,69).…”

Section: Vegf-bmentioning

confidence: 62%

“…The metabolic phenotype of the Vegfb Ϫ/Ϫ mice is further discussed below (see section 4). Cardiac overexpression of VEGF-B induced myocardial hypertrophy, both in mice and rats, albeit through an unclear molecular mechanism (14,56,62,69,121). Increased coronary growth was also detected in cardiac-specific VEGF-B transgenic rats but not mice (14,62).…”

Section: Vegf-bmentioning

confidence: 95%

Endothelial Fatty Acid Transport: Role of Vascular Endothelial Growth Factor B

et al. 2013

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Dietary lipids present in the circulation have to be transported through the vascular endothelium to be utilized by tissue cells, a vital mechanism that is still poorly understood. Vascular endothelial growth factor B (VEGF-B) regulates this process by controlling the expression of endothelial fatty acid transporter proteins (FATPs). Here, we summarize research on the role of the vascular endothelium in nutrient transport, with emphasis on VEGF-B signaling.

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The effects of VEGF-R1 and VEGF-R2 ligands on angiogenic responses and left ventricular function in mice

Abstract: 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).

Cited by 47 publications

References 28 publications

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Endothelial Fatty Acid Transport: Role of Vascular Endothelial Growth Factor B

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