Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction

Hao, Xiaoyan; Silva, Eduardo A.; Månsson‐Broberg, Agneta; Grinnemo, Karl‐Henrik; Siddiqui, Anwar J.; Dellgren, Göran; Wärdell, Eva; Brodin, Lars Åke; Mooney, David J.; Sylvén, Christer

doi:10.1016/j.cardiores.2007.03.028

Cited by 342 publications

(259 citation statements)

References 31 publications

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“…Interestingly, controlled sequential release of PDGF-BB together with VEGF-A was shown to induce mature blood vessels and improve cardiac function in cardiac ischemia in mice (33). Carefully manipulating the delivery timing and method of PDGF and/ or its downstream signaling effectors can potentially serve as a therapeutical option for heart repair.…”

Section: Discussionmentioning

confidence: 99%

PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts

Kim¹,

Wu²,

Zhang³

et al. 2010

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

179

187

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A zebrafish heart can fully regenerate after amputation of up to 20% of its ventricle. During this process, newly formed coronary blood vessels revascularize the regenerating tissue. The formation of coronary blood vessels during zebrafish heart regeneration likely recapitulates embryonic coronary vessel development, which involves the activation and proliferation of the epicardium, followed by an epithelial-to-mesenchymal transition. The molecular and cellular mechanisms underlying these processes are not well understood. We examined the role of PDGF signaling in explantderived primary cultured epicardial cells in vitro and in regenerating zebrafish hearts in vivo. We observed that mural and mesenchymal cell markers, including pdgfrβ, are up-regulated in the regenerating hearts. Using a primary culture of epicardial cells derived from heart explants, we found that PDGF signaling is essential for epicardial cell proliferation. PDGF also induces stress fibers and loss of cell-cell contacts of epicardial cells in explant culture. This effect is mediated by Rhoassociated protein kinase. Inhibition of PDGF signaling in vivo impairs epicardial cell proliferation, expression of mesenchymal and mural cell markers, and coronary blood vessel formation. Our data suggest that PDGF signaling plays important roles in epicardial function and coronary vessel formation during heart regeneration in zebrafish.epicardium | mesenchymal cells | mural cells | zebrafish heart regeneration C oronary heart disease is among the leading causes of disability and mortality in the United States and worldwide (1). Scars form in injured human hearts, which results in decreased cardiac performance and the eventual development of heart failure (2). In contrast to humans, zebrafish and newts have remarkable regenerative abilities (3, 4). After 20% resection of the ventricle, zebrafish fully regenerate lost heart tissue (3, 4). During this process, newly formed coronary blood vessels vascularize the regenerating myocardium (5, 6). Expression of the embryonic epicardial markers tbx18 and raldh2 is induced in the epicardium of adult regenerating hearts (5, 6), suggesting that an embryonic gene expression program in the epicardium is activated in response to injury. This activation starts throughout the entire ventricle and gradually becomes localized to the apex. The activated epicardium proliferates from 3 to 7 d postamputation (dpa) (5). A previous study suggested that the activated epicardium undergoes an epithelial-to-mesenchymal transition (EMT) and subsequently contributes to newly formed coronary blood vessels (5). The lineages of the different cell types in blood vessels formed during zebrafish heart regeneration have not yet been conclusively determined.Zebrafish heart regeneration, at least in part, likely recapitulates embryonic heart development. EMT is a key step during heart development in mice and chicks, wherein the epicardium forms epicardium-derived cells (EPDCs), which then differentiate into fibroblasts, smooth muscle cells (7-9)...

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Section: Discussionmentioning

confidence: 99%

PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts

Kim¹,

Wu²,

Zhang³

et al. 2010

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

179

187

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“…In order to form more stable vessels with supporting smooth muscles cells, dual delivery of angiogenic growth factors using injectable hydrogels has been explored to treat MI. Hao et al encapsulated vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) in alginate hydrogels by mixing a solution of purified alginate and growth factors with a calcium sulfate solution upon injection into the myocardium [92]. The rationale for choosing these two molecules was to first stimulate endothelial vessel formation with VEGF delivery, followed by smooth muscle cell recruitment with PDGF delivery to support the immature vessels.…”

Section: Angiogenic Factorsmentioning

confidence: 99%

Injectable Acellular Hydrogels for Cardiac Repair

Tous

Purcell

Ifkovits

et al. 2011

J. of Cardiovasc. Trans. Res.

150

143

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Injectable hydrogels are being developed as potential translatable materials to influence the cascade of events that occur after myocardial infarction. These hydrogels, consisting of both synthetic and natural materials, form through numerous chemical crosslinking and assembly mechanisms and can be used as bulking agents or for the delivery of biological molecules. Specifically, a range of materials are being applied that alter the resulting mechanical and biological signals after infarction and have shown success in reducing stresses in the myocardium and limiting the resulting adverse left ventricular (LV) remodeling. Additionally, the delivery of molecules from injectable hydrogels can influence cellular processes such as apoptosis and angiogenesis in cardiac tissue or can be used to recruit stem cells for repair. There is still considerable work to be performed to elucidate the mechanisms of these injectable hydrogels and to optimize their various properties (e.g., mechanics and degradation profiles). Furthermore, although the experimental findings completed to date in small animals are promising, future work needs to focus on the use of large animal models in clinically relevant scenarios. Interest in this therapeutic approach is high due to the potential for developing percutaneous therapies to limit LV remodeling and to prevent the onset of congestive heart failure that occurs with loss of global LV function. This review focuses on recent efforts to develop these injectable and acellular hydrogels to aid in cardiac repair.

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“…Wound revascularization depends on the precisely balanced interplay of several proangiogenic growth factors like VEGF and PDGF [34] and on a proper growth factor gradient [35] to direct blood vessel growth. Therefore, a protein therapy might be disadvantageous because locally administered proteins experience rapid dilution and degradation processes [36], which may cause an inhomogeneous gradient.…”

Section: Discussionmentioning

confidence: 99%

The angiogenic response to PLL-g-PEG-mediated HIF-1α plasmid DNA delivery in healthy and diabetic rats

et al. 2013

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Impaired angiogenesis is a major clinical problem and affects wound healing especially in diabetic patients. Improving angiogenesis is a reasonable strategy to increase diabetes-impaired wound healing. Recently, our lab described a system of transient gene expression due to pegylated poly-l-lysine (PLL-g-PEG) polymer-mediated plasmid DNA delivery in vitro. Here we synthesized peptide-modified PLL-g-PEG polymers with two functionalities, characterized them in vitro and utilized them in vivo via a fibrin-based delivery matrix to induce dermal wound angiogenesis in diabetic rats. The two peptides were 1) a TG-peptide to covalently bind these nanocondensates to the fibrin matrix (TG-peptide) for a sustained release and 2) a polyR peptide to improve cellular uptake of these nanocondensates. In order to induce angiogenesis in vivo we condensed modified and non-modified polymers with plasmid DNA encoding a truncated form of the therapeutic candidate gene hypoxia-inducible transcription factor 1 (HIF-1 ). HIF-1 is the primarily oxygen-dependent regulated subunit of the heterodimeric transcription factor HIF-1, which controls angiogenesis among other physiological pathways. The truncated form of HIF-1 lacks the oxygen-dependent degradation domain (ODD) and therefore escapes degradation under normoxic conditions. PLL-g-PEG polymer-mediated HIF-1 -ΔODD plasmid DNA delivery was found to lead to a transiently induced gene expression of angiogenesis-related genes Acta2 and Pecam1 as well as the HIF-1 target gene Vegf in vivo. Furthermore, HIF-1 gene delivery was shown to enhance the number endothelial cells and smooth muscle cells -precursors for mature blood vessels -during wound healing. We show that -depending on the selection of the therapeutic target gene -PLL-g-PEG nanocondensates are a promising alternative to viral DNA delivery approaches, which might pose a risk to health. AbstractImpaired angiogenesis is a major clinical problem and affects wound healing especially in diabetic patients. Improving angiogenesis is a reasonable strategy to increase diabetes-impaired wound healing. Recently, our lab described a system of transient gene expression due to pegylated poly-L-lysine (PLL-g-PEG) polymermediated plasmid DNA delivery in vitro. Here we synthesized peptide-modified PLLg-PEG polymers with two functionalities, characterized them in vitro and utilized them in vivo via a fibrin-based delivery matrix to induce dermal wound angiogenesis in diabetic rats. The two peptides were 1) a TG-peptide to covalently bind these nanocondensates to the fibrin matrix (TG-peptide) for a sustained release and 2) a polyR peptide to improve cellular uptake of these nanocondensates. In order to induce angiogenesis in vivo we condensed modified and non-modified polymers with plasmid DNA encoding a truncated form of the therapeutic candidate gene hypoxiainducible transcription factor 1α (HIF-1α). HIF-1α is the primarily oxygen-dependent regulated subunit of the hetero-dimeric transcription factor HIF-1, which controls angiogenesis...

show abstract

Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction

Cited by 342 publications

References 31 publications

PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts

PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts

Injectable Acellular Hydrogels for Cardiac Repair

The angiogenic response to PLL-g-PEG-mediated HIF-1α plasmid DNA delivery in healthy and diabetic rats

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