Activation of PKCα and PI3K Kinases in Hypertrophic and Nodular Port Wine Stain Lesions

Yin, Rong; Gao, Lin; Tan, Wenbin; Guo, Wei; Zhao, Tao; Nelson, J. Stuart; Wang, Gang

doi:10.1097/dad.0000000000000785

Cited by 22 publications

(30 citation statements)

References 31 publications

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“…and ), suggesting that molecular phenotypes rather than morphological features are possibly underlying the laser‐resistant mechanisms for those blood vessels. We recently characterized a spectrum of pathological and molecular phenotypes of PWS blood vessels (i) the alterations of entire physiological milieu of human skin, including ECs, smooth muscle cells and extracellular matrix, in infantile PWS ; (ii) the activation of the mitogen‐activated protein kinases, PKCα, and phosphoinositide 3‐kinase in PWS blood vessels ; (iii) upregulation of membrane trafficking and exocytosis of PWS ECs ; and (iv) expression of surface markers of EphB1/EphrinB2/CD133/CD166 on PWS ECs . These are the first steps toward uncovering the molecular pathogenesis of PWS, which are likely associated with laser‐resistant PWS phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Laser‐Resistant Port Wine Stain Blood Vessels Using In Vivo Reflectance Confocal Microscopy

Huang

Xiang

et al. 2019

Lasers Surg Med

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Background and Objectives Port wine stain (PWS) is a congenital vascular malformation of the human skin. Laser is the treatment of choice for PWS. Laser‐resistant PWS is one crucial factor accounting for inadequate treatment outcome, which needs to be fully characterized. This study aims to quantitatively characterize the morphology of laser‐resistant PWS blood vessels in the upper papillary dermis using in vivo reflectance confocal microscopy (RCM). Study Design/Materials and Methods A total of 42 PWS subjects receiving laser treatment from August 2016 through July 2018 were enrolled into this study. Thirty‐three subjects had facial PWS; nine had extremity PWS. All subject's PWS received multiplex 585/1,064 nm laser treatment. RCM images were taken before and after treatment. The density, diameter, blood flow, and depth of PWS blood vessels were analyzed. Results We found 44.4% PWS on the extremities (four out of nine subjects) were laser‐resistant, which was significantly higher (P < 0.001) when compared with those PWS on the face (15.2%, 5 out of 33 subjects). The laser‐resistant facial PWS blood vessels had significantly higher blood flow (1.35 ± 0.26 U vs. 0.89 ± 0.22 U, P < 0.001), larger blood vessel diameters (109.60 ± 18.24 µm vs. 84.36 ± 24.04 µm, P = 0.033) and were located deeper in the skin (106.01 ± 13.87 µm vs. 87.82 ± 12.57 µm, P < 0.001) in the skin when compared with laser‐responsive PWS on the face. The average PWS blood vessel density (17.01 ± 4.63/mm2 vs. 16.61 ± 4.44/mm2, P = 0.857) was not correlated to the laser resistance. Conclusions Laser‐resistant PWS blood vessels had significantly higher blood flow, larger diameters, and were located deeper in the skin. RCM can be a valuable tool for a prognostic evaluation on laser‐resistant lesions before treatment, thereby providing guidance for tailored laser treatment protocols, which may improve the therapeutic outcome. The limitations for this study include relative small sample size and acquisitions of different blood vessels before and after 2 months of treatment. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Characterization of Laser‐Resistant Port Wine Stain Blood Vessels Using In Vivo Reflectance Confocal Microscopy

Huang

Xiang

et al. 2019

Lasers Surg Med

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“…There is subsequent activation of various kinases during different stages of PWS [7]: (1) JNKs and ERKs are firstly and consecutively activated in all PWS tissues, which may contribute to both the pathogenesis and progressive development of PWS; (2) AKT and PI3K are subsequently activated and may be involved in hypertrophic PWS blood vessels; and (3) phosphoinositide phospholipase C γ subunit (PLC-γ), PI3K and protein kinase C (PKC) are activated in the most advanced stage of PWS and participate in nodule formation [7,8]. There is a progressive activation of PKCα, PI3K, 3-phosphoinositide dependent protein kinase-1 (PDPK1) and PLC-γ and increased expression of protein phosphatase 2 and diglyceride from normal skin to hypertrophic and nodular PWS [8]. The aberrant activations of these kinases expand from single layer ECs into entire blood vessels stroma and fibroblasts during the progression of PWS nodular formation [8].…”

Section: Pathological Phenotypes Of Pws/swsmentioning

confidence: 99%

“…Seizures, glaucoma, cerebral cortex atrophy, developmental delay and intellectual impairments commonly occur in infancy and may worsen with age [5,6]. The recent discoveries of somatic mutations in the guanine nucleotide-binding protein, G alpha subunit q ( GNAQ ) (R183Q), phosphatidylinositol 3-kinase ( PI3K ) and activation of mitogen-activated protein kinase (MAPK) and PI3K pathways in skin lesions of PWS/SWS have greatly enhanced our understanding of the pathogenesis of the malformations [7,8,9,10]. In this review, we will summarize our current understanding of the genetic mutations of GNAQ and PI3K and their roles in activation of MAPK/PI3K in the pathogenesis and progression of PWS/SWS as well as the development of anti-angiogenesis in combination with pulsed dye laser (PDL) for the treatment of PWS/SWS.…”

Section: Introductionmentioning

confidence: 99%

The Pathogenesis of Port Wine Stain and Sturge Weber Syndrome: Complex Interactions between Genetic Alterations and Aberrant MAPK and PI3K Activation

Nguyen

Hochman

Mihm

et al. 2019

IJMS

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Port wine stain (PWS) is a congenital vascular malformation involving human skin. Approximately 15–20% of children a facial PWS involving the ophthalmic (V1) trigeminal dermatome are at risk for Sturge Weber syndrome (SWS), a neurocutaneous disorder with vascular malformations in the cerebral cortex on the same side of the facial PWS lesions. Recently, evidence has surfaced that advanced our understanding of the pathogenesis of PWS/SWS, including discoveries of somatic genetic mutations (GNAQ, PI3K), MAPK and PI3K aberrant activations, and molecular phenotypes of PWS endothelial cells. In this review, we summarize current knowledge on the etiology and pathology of PWS/SWS based on evidence that the activation of MAPK and/or PI3K contributes to the malformations, as well as potential futuristic treatment approaches targeting these aberrantly dysregulated signaling pathways. Current data support that: (1) PWS is a multifactorial malformation involving the entire physiological structure of human skin; (2) PWS should be pathoanatomically re-defined as “a malformation resulting from differentiation-impaired endothelial cells with a progressive dilatation of immature venule-like vasculatures”; (3) dysregulation of vascular MAPK and/or PI3K signaling during human embryonic development plays a part in the pathogenesis and progression of PWS/SWS; and (4) sporadic low frequency somatic mutations, such as GNAQ, PI3K, work as team players but not as a lone wolf, contributing to the development of vascular phenotypes. We also address many crucial questions yet to be answered in the future research investigations.

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“…Actually, in the (few) families studied so far, an inherited gene is thought to predispose the individual, while a second somatic mutation to result in the PWS [24]. Among these somatic mutations, the post-zygotic mutation on G alpha subunit q (GNAQ) and the mutation on the phosphatidylinositol 3kinase (PI3K) pathways and their interactions are considered the most important ones [80,127,144]. The alterations in those pathways would lead to a dysregulation of vascular development during embryogenesis, which is at the base of SWS development.…”

Section: Etiopathogenesismentioning

confidence: 99%

Sturge-Weber syndrome: an update on the relevant issues for neurosurgeons

et al. 2020

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Purpose Sturge-Weber syndrome (SWS) is a neurocutaneous facomatosis characterized by facial and leptomeningeal angioma, glaucoma, seizures, and neurological disability. Therefore, a challenging multidisciplinary interaction is required for its management. The goal of this paper is to review the main aspects of SWS and to present an illustrative pediatric series. Methods The pertinent literature has been analyzed, focused mainly on etiopathogenesis, pathology, clinical features, diagnostic tools, management, and outcome of the disease. Moreover, a series of 11 children operated on for refractory epilepsy between 2005 and 2015 (minimum follow-up 5 years, mean follow-up 9.6 years) is reported. The series consists of six boys and five girls with 6.5-month and 16.2-month mean age at seizure onset and at surgery, respectively. Seizures affected all children, followed by hemiparesis and psychomotor delay (81%), glaucoma (54%), and other neurological deficits (45%). Results All children underwent hemispherectomy (anatomical in three cases, functional in two cases, hemispherotomy in six cases); one patient needed a redo hemispherotomy. Mortality was nil; disseminated intravascular coagulation and interstitial pneumonia occurred in one patient each; three children had subdural fluid collection. Eight patients (72%) are in the ILAE Class 1 (completely seizure and aura free), two in Class 2 (only auras, no seizure), and one in Class 3 (1-3 seizure days per year). AEDs discontinuation was possible in 73% of cases. The most important news from the literature concerned the pathogenesis (role of the mutation of the GNAQ gene in the abnormal SWS vasculogenesis), the clinical findings (the features and pathogenesis of the stroke-like episodes are being understood), the diagnostic tools (quantitative MRI and EEG), and both the medical (migraine, seizures) and surgical management (epilepsy). The epileptic outcome of SWS patients is very good (80% are seizure-free), if compared with other hemispheric syndromes. The quality of life is affected by the neurological and cognitive deficits. Conclusions SWS still is an etiological and clinical challenge. However, the improvements over the time are consistent. In particular, the neurosurgical treatment of refractory epilepsy provides very good results as long as the indication to treatment is correct.

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Activation of PKCα and PI3K Kinases in Hypertrophic and Nodular Port Wine Stain Lesions

Cited by 22 publications

References 31 publications

Characterization of Laser‐Resistant Port Wine Stain Blood Vessels Using In Vivo Reflectance Confocal Microscopy

Characterization of Laser‐Resistant Port Wine Stain Blood Vessels Using In Vivo Reflectance Confocal Microscopy

The Pathogenesis of Port Wine Stain and Sturge Weber Syndrome: Complex Interactions between Genetic Alterations and Aberrant MAPK and PI3K Activation

Sturge-Weber syndrome: an update on the relevant issues for neurosurgeons

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