The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors

Pola, Roberto; Ling, Leona; Silver, Marcy; Corbley, Michael J.; Kearney, Marianne; Pepinsky, R. Blake; Shapiro, Reneé; Taylor, Frederick R.; Baker, Darren P.; Asahara, Takayuki; Isner, Jeffrey M.

doi:10.1038/89083

Cited by 559 publications

(580 citation statements)

References 44 publications

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“…Other studies have shown that in the setting of ischemia, vessels formed in the presence of Shh had similar characteristics as the ones described here (ie, larger-diameter vessels and more often coated with SMCs). 50,58 In our study, injection of the arterial cocktail without hMAPCs also induced effects on the endogenous mouse vascular cells but, importantly, the effects were more pronounced in the presence of hMAPCs. We hypothesize that, in addition to their direct contribution to arterial endothelium, hMAPCs (similar to other stem cells 45 ), and more so when cultured in arterial media, had trophic effects on endogenous cells through secretion of PDGF-BB and TGF-␤1.…”

Section: Discussionmentioning

confidence: 87%

“…The involvement of those pathways was further substantiated by the differential expression of many of the pathway members in hMAPCs and hAC133 ϩ cells. Increased expression of the patched receptors in hMAPCs may be the result of an autocrine positive feedback loop 49,50 driven by hMAPCderived Shh. Intriguingly, while Notch-1 was exclusively expressed in hMAPCs, Notch-4 was significantly underexpressed in hMAPCs in comparison with hAC133 ϩ cells.…”

Section: Discussionmentioning

confidence: 99%

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In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

Aranguren

Luttun

Clavel

et al. 2006

Blood

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IntroductionThe vascular system is a bipolar complex network of arteries that transport oxygen-rich blood to all tissues and veins that bring oxygendeprived blood back to the heart. 1 Because of this bipolar set-up, arteries and veins feature anatomic and physiological differences. Unlike venous endothelium, arterial endothelium is surrounded by several layers of smooth muscle cells (SMCs), separated by elastic laminae, and embedded in a thick layer of fibrillar collagen. 2 Moreover, both vessel types have a differential susceptibility to atherosclerotic disease, possibly due to exposure to different levels of shear stress. Arterial and venous endothelial cells (ECs) also have a distinct molecular signature, and such molecular specification occurs before the onset of blood flow. 3 Indeed, arteriovenous (AV) specification of ECs is accomplished early in development and is associated with the expression of a specific complement of factors: venous endothelium is characterized by the expression of EphB4, 4 Lefty-1, 5 Lefty-2, 5 COUP-TFII, 6 and MYO1-␤, 5 and arterial ECs express high levels of Notch 1 and 4, 7 Dll-4, 8 EphrinB1 and EphrinB2, 4 Jagged-1 and -2, 7 connexin-40, and Hey-2 (gridlock zebrafish ortholog). 9,10 Studies in Xenopus, zebrafish, and mice have revealed that, besides blood flow, 11 vessel-intrinsic cues and-later in development-signals from outside the vasculature 12,13 are implicated in defining arterial or venous fate such as members of the TGF-␤ pathway, 14,15 VEGF isoforms,13,[16][17][18]17 angiopoietins, 19 the Notch pathway, 7,9,20-22 the patched pathway, 20 and COUP-TFII, a member of the orphan nuclear receptor superfamily. 6 Although it has been shown that some of these pathways are well conserved from zebrafish to mouse, less information is available on whether they have a similar role in humans. Because these molecular differences between arterial and venous ECs exist independently of blood flow and some of these factors work in an EC-intrinsic way, 2 it should be possible to manipulate some or all of these to endow ECs with an arterial or venous fate. Consistent with this notion, recent studies have suggested that arterial markers can be induced in primary mature ECs. 5,13,21,23,24 Many different stem cell populations, including bone marrow (BM) mononuclear cells, AC133 ϩ endothelial progenitor cells, and embryonic stem cells have the potential to differentiate in vitro and in vivo into mature and functional ECs. 4,[25][26][27][28] We have recently described another stem cell population, multipotent adult progenitor cells (MAPCs), that differentiates into most somatic cell types, including functional ECs, in vitro and in vivo. [29][30][31][32][33] The question of whether and how these stem cells can be coaxed into arterial or venous ECs has thus far not been addressed. In this study, we analyzed the in vitro and in vivo arterial and venous endothelial differentiation of human MAPCs (hMAPCs) and hAC133 ϩ cells. Materials and methodsAdditional and extended descriptions of methods are inc...

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

Aranguren

Luttun

Clavel

et al. 2006

Blood

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“…Intriguingly, upregulation in Shh and Ptch1 transcription has also been detected in adult fully differentiated muscle upon the induction of regeneration following ischemic injury. During this process, HH plays a crucial role in promoting angiogenesis and increasing satellite cell number at the affected site (Pola et al, 2003(Pola et al, , 2001Straface et al, 2009). By contrast, SMO inhibition by cyclopamine treatment in injured animals results in muscle fibrosis and increased inflammation (Straface et al, 2009).…”

Section: Musclementioning

confidence: 99%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

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“…Previous research showed that the morphogen Sonic hedgehog (Shh) acts upstream of VEGF (Pola et al, 2001;Lawson et al, 2002). Zebrafish embryos mutant for Shh show diminished arterial endothelial differentiation due to impaired endothelial VEGF signaling (Lawson et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency

et al. 2009

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Objective Previous research in fetuses with increased nuchal translucency (NT) showed abnormal lymphatic endothelial differentiation characteristics, including increased vascular endothelial growth factor (VEGF)-A expression, and aberrant smooth muscle cells (SMCs) surrounding enlarged jugular lymphatic sacs (JLS). We hypothesized that abnormal Sonic hedgehog (Shh) expression would result in altered VEGF-A signaling in the lymphatic endothelial cells of the JLS and that aberrant acquisition of SMCs could be caused by downregulation of forkhead transcription factor FOXC2 and upregulation of platelet-derived growth factor (PDGF)-B in the lymphatic endothelial cells of the JLS.Methods Five trisomy 21 fetuses and four controls were investigated using immunohistochemistry for Shh, VEGF-A, FOXC2 and PDGF-B expression in the lymphatic endothelial cells of the JLS.Results An increased Shh, VEGF-A and PDGF-B expression, and decreased FOXC2 expression were shown in the lymphatic endothelial cells of the JLS of the trisomic fetuses.Conclusions Increased Shh and VEGF-A expression is correlated with an aberrant lymphatic endothelial differentiation in trisomy 21 fetuses. The SMCs surrounding the JLS can possibly be explained by an increase of PDGF-B-induced SMC recruitment and/or differentiation. This underscores earlier findings that indicate the loss of lymphatic identity in trisomy 21 fetuses and a shift towards a blood vessel wall phenotype.

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The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors

Cited by 559 publications

References 44 publications

In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

Roles for Hedgehog signaling in adult organ homeostasis and repair

Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency

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