PDGF‐B signaling is important for murine cardiac development: Its role in developing atrioventricular valves, coronaries, and cardiac innervation

Akker, Nynke M. S. van den; Winkel, Leah C.J.; Nisancioglu, Maya H.; Maas, Saskia; Wisse, Lambertus J.; Armulik, Annika; Poelmann, Robert E.; Lie-Venema, Heleen; Betsholtz, Christer; Groot, Adriana C. Gittenberger‐de

doi:10.1002/dvdy.21436

Cited by 82 publications

(56 citation statements)

References 57 publications

(87 reference statements)

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“…PDGFR-␣ is important mainly for nonneuronal cardiac neural crest development (Morrison-Graham et al 1992). PDGFR-␤ and PDGF-B appear to play a role in neuronal cardiac neural crest development, as both PDGFR-␤ and PDGF-B knockouts display abnormal cardiac innervation (Van den Akker et al 2008). Thus, PDGFR-␣ and PDGFR-␤ signaling appear to have complementary roles in cardiac neural crest development.…”

Section: Role Of Pdgf Signaling In Gastrulation and Formation Of Cranmentioning

confidence: 99%

“…Studies using PDGFR-␣ signaling mutants implicate both Src and PI3K as critical mediators of OP proliferation (Klinghoffer et al 2002). Transgenic mice expressing different amounts of PDGF-A in the CNS have revealed that OPs proliferate until the growth factor becomes limiting; i.e., when OPs "consume" PDGF-A at a faster rate than it is produced (van Heyningen et al 2001). When available PDGF is limiting (or withdrawn experimentally), OPs differentiate into myelinating oligodendrocytes.…”

Section: Role Of Pdgfs In Glial Cell Development and Neuroprotectionmentioning

confidence: 99%

“…However, recent analyses of the complex heart phenotype in PDGF-B and PDGFR-␤ knockout embryos suggest a general problem with epicardial derivatives. This leads to complex malformations including ventricular septum defects and abnormal development of the atrioventricular valves (Van den Akker et al 2008). Combined with the PDGF-B/ PDGFR-␤ expression patterns in the developing heart (Van Den Akker et al 2005), these defects suggest that PDGF-B produced by developing coronary endothelium and endocardium may play a role in epicardial epithelial-tomesenchymal transition (EMT) and recruitment of epicardium-derived mesenchymal cells into the myocardium.…”

Section: Role Of Pdgf-b and Pdgfr-␤ In The Development Of The Cardiovmentioning

confidence: 99%

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Role of platelet-derived growth factors in physiology and medicine

Andræ¹,

Gallini²,

Betsholtz³

2008

Genes Dev.

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2,074

1,898

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Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-␣ signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-␤ signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial-mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.Platelet-derived growth factor (PDGF) was identified more than three decades ago as a serum growth factor for fibroblasts, smooth muscle cells (SMCs), and glia cells (Kohler and Lipton 1974;Ross et al. 1974;Westermark and Wasteson 1976). Human PDGF was originally identified as a disulfide-linked dimer of two different polypeptide chains, A and B, separable using reversed phase chromatography (Johnsson et al. 1982). The B-chain (PDGF-B) was characterized by amino acid sequencing, revealing a close homology between PDGF-B and the product of the retroviral oncogene v-sis of simian sarcoma virus (SSV) (Doolittle et al. 1983;Waterfield et al. 1983). Subsequent studies confirmed that the human cellular counterpart (c-sis) was identical to PDGF-B and that autocrine PDGF activity was sufficient for SSV transformation in vitro. This was a paradigm-shifting discovery about the relationship between neoplastic cell transformation and normal growth control. For the first time, the importance of autocrine growth stimulation in neoplastic transformation was demonstrated. As discussed below, it is now well established that autocrine PDGF stimulation plays a role also in some human cancers.PDGF-A was characterized by cDNA cloning ). This resolved a paradoxical lack of correlation between secretion of PDGF-like growth factors from tumor cell lines and their expression of c-sis; it turned out that most such cell lines express PDGF-A and secrete PDGF-AA homodimers ). Together with the demonstration that PDGF-BB homodimers are produced by SSV-transformed or PDGF-Bexpressing cells, these results showed that the PDGF...

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Section: Role Of Pdgf Signaling In Gastrulation and Formation Of Cranmentioning

confidence: 99%

Section: Role Of Pdgfs In Glial Cell Development and Neuroprotectionmentioning

confidence: 99%

Section: Role Of Pdgf-b and Pdgfr-␤ In The Development Of The Cardiovmentioning

confidence: 99%

See 1 more Smart Citation

Role of platelet-derived growth factors in physiology and medicine

Andræ¹,

Gallini²,

Betsholtz³

2008

Genes Dev.

Self Cite

2,074

1,898

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“…Interestingly, pdgfrβ is expressed in the epicardium of developing embryonic mouse hearts and is required for coronary artery formation (21,22). The expression of pdgfrβ in the wound and the epicardium (Fig.…”

Section: Mural Cells Are Present In Coronary Vessels During Zebrafishmentioning

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.

182

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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“…This is also supported by studies using transgenic mice [11]. We have shown that the sinus venosusderived endothelial cells express the "arterial" Notch1, underlining the plasticity of these cells [9]. The discussion on the origin of the coronary endothelium is kept alive as specific compartments produce restricted numbers of ECs [12,13].…”

Section: Endothelial Cellsmentioning

confidence: 80%

The Arterial Epicardium: A Developmental Approach to Cardiac Disease and Repair

Groot

Winter

Goumans

et al. 2016

Etiology and Morphogenesis of Congenital Heart Disease

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The significance of the epicardium that covers the heart and the roots of the great arteries should not be underestimated as it is a major component with impact on development, disease, and repair. The epicardium differentiates from the proepicardial organ located at the venous pole (vPEO). The differentiation capacities of the vPEO into epicardium-derived cells (EPDCs) have been extensively described. A hitherto escaped part of the epicardium derives from a second proepicardial organ located at the arterial pole (aPEO) and covers the intrapericardial part of the aorta and pulmonary trunk. In avian and mouse embryos, disturbance of epicardium differentiation causes a spectrum of cardiac anomalies including coronary artery abnormalities, deficient annulus fibrosis with rhythm disturbances, valve malformations, and non-compaction cardiomyopathies. Late in prenatal life the epicardium becomes dormant, losing the activity of many genes.In human cardiac diseases, both arterial and venous epicardium can be activated again into EPDCs. The epicardial reactivation observed after experimental

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PDGF‐B signaling is important for murine cardiac development: Its role in developing atrioventricular valves, coronaries, and cardiac innervation

Cited by 82 publications

References 57 publications

Role of platelet-derived growth factors in physiology and medicine

Role of platelet-derived growth factors in physiology and medicine

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

The Arterial Epicardium: A Developmental Approach to Cardiac Disease and Repair

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