Low-Dosage Inhibition of Dll4 Signaling Promotes Wound Healing by Inducing Functional Neo-Angiogenesis

The Notch pathway is definitely required for normal vascular development. Although the contribution of Notch in postnatal angiogenesis is the focus of intense investigation, the implication of Notch in reparative neovascularization in the skin remains unexplored. In this study, we investigated Notch changes using a skin model of ischemia. Thirty Sprague-Dawley rats were divided into two groups. In the surgery group (n = 24), a caudally based dorsal skin flap was raised and sutured back into its initial position. In the control group, no surgical procedure was performed. Tissue biopsies were obtained at different time intervals. Tissue specimens were assessed for Delta-like ligand 4 (DLL4) and vascular endothelial growth factor (VEGF) gene expression by real-time polymerase chain reaction (PCR). Immunohistochemical staining was used for detection of DLL4 in tissue materials. Quantitative assessment of skin flap microvasculature was made. Compared with normoperfused tissue, VEGF and DLL4 expressions increased significantly (p < 0.01). Immunohistochemical analysis revealed weak and patchy expression of DLL4 in microvascular endothelial cells of normoperfused tissues. Conversely, DLL4 expression was upregulated in capillary endothelial cells after ischemia. In conclusion, in this study we have shown that the Notch ligand DLL4 is upregulated in skin tissue after ischemia. A deeper understanding of these fundamental principles will aid in the development of new avenues for the treatment of blood vessel-related skin pathologies.

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“…DLL4 inhibition accelerated wound regeneration by creating a neo-vasculature that has a slight increase in vascular density. 17 …”

Section: Discussionmentioning

confidence: 99%

The Notch pathway is a critical regulator of angiogenesis in a skin model of ischemia

et al. 2015

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“…When these mice reached 6 weeks, recombinase cre activity was induced by daily i.p. tamoxifen administration (50 mg/kg in 10% ethanol plus 90% cremophor), during 5 days as in [31]. Tamoxifen treated cre-negative mice were used as controls.…”

Section: Methodsmentioning

confidence: 99%

Delta-like 4/Notch signaling promotes Apc Min/+ tumor initiation through angiogenic and non-angiogenic related mechanisms

et al. 2017

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BackgroundDelta like 4 (Dll4)/Notch signaling is a key regulator of tumor angiogenesis. Additionally, the role of Dll4 has been studied on tumor stem cells. However, as these cells are implicated in tumor angiogenesis, it is conceivable that the effect of Dll4 on these cells may be a consequence of its angiogenic function. Our aim was to evaluate the expression and dissect the functions of Dll4 in the Apc Min/+ model of colorectal cancer.MethodsWe evaluated the protein expression pattern of Dll4 and other Notch members in the Apc Min/+ tumors relatively to the normal gut and compared endothelial-specific with ubiquitous Dll4 knockout mice on an Apc Min/+ background.ResultsAll Notch pathway members were present in the normal small and large intestine and in the adenomas of the same regions. Dll4, all Notch receptors and Hes1 expression seemed upregulated in the tumors, with some regional differences. The same members and Hes5, instead of Hes1, presented ectopic expression in the tumor parenchyma. Dll4 expression was most pronounced in the tumor cells but it was also present in the tumor blood vessels and in other stromal cells. Ubiquitous and endothelial-specific Dll4 deletion led to an equivalent reduction of tumor growth because of a similarly marked tumoral angiogenic phenotype promoting non-productive vasculature and consequently hypoxia and apoptosis. The ubiquitous Dll4 inhibition led to a stronger decrease of tumor multiplicity than the endothelial-specific deletion by further reducing tumor proliferation and tumor stem cell density through upregulation of the cyclin-dependent kinase inhibitors 1C and 1B and downregulation of Myc, Cyclin D1 and D2 independently of β-catenin activation. This phenotype was associated to the observed increased epithelial differentiation deviated towards the secretory lineages by Atoh1 and Klf4 upregulation only in the ubiquitous Dll4 mutants.ConclusionsDll4 seems to promote Apc Min/+ tumorigenesis through both angiogenic and non-angiogenic related mechanisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-3036-0) contains supplementary material, which is available to authorized users.

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“…11 Recent animal studies have shown a dosedependent response to anti-DLL4 therapy resulting in an improved rate of wound healing. 12 A controversial topic is to give a growth factor prophylactically to accelerate a normal wound to heal faster or to reduce the risk of future wound complication in a person who is prone to poor healing. This clinical situation is similar to giving prophylactic antibiotics in cleancontaminated surgical procedures to reduce infection rates.…”

Section: Growth-factor Use In the Head And Neckmentioning

confidence: 99%

Update in Wound Healing in Facial Plastic Surgery

Hershcovitch

Hom

2012

Arch Facial Plast Surg

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Low-Dosage Inhibition of Dll4 Signaling Promotes Wound Healing by Inducing Functional Neo-Angiogenesis

Cited by 37 publications

References 41 publications

The Notch pathway is a critical regulator of angiogenesis in a skin model of ischemia

The Notch pathway is a critical regulator of angiogenesis in a skin model of ischemia

Delta-like 4/Notch signaling promotes Apc Min/+ tumor initiation through angiogenic and non-angiogenic related mechanisms

Update in Wound Healing in Facial Plastic Surgery

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