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

Rong Yin,Lin Gao,Gang Wang,Wei Guo,Jhon Stuart Nelson,Tao Zhao,Wenbin Tan

doi:10.1097/dad.0000000000000785

Abstract

:Port wine stain (PWS) is a congenital, progressive vascular malformation. Many patients with PWS develop hypertrophy and discrete nodularity during their adult life, but the mechanism(s) remain incompletely understood. In this study, we attempted to investigate activation status of PKCα, PI3K, PDPK1 and PLC-γ and protein levels of PP2A and DAG to explore their potential roles in the formation of hypertrophic and nodular PWS lesions. We found phosphorylated levels of PKCα, PI3K, PDPK1, and PLC-γ and protein levels of PP2A and DAG showed moderate increases in the endothelial cells of hypertrophic PWS as compared to the adjacent normal skin. These increases extended throughout the entire stroma of blood vessels in PWS nodules. Many proliferating cells, such as fibroblasts, also showed strong activation of PKCα, PI3K, PDPK1 and PLC-γ and upregulations of PP2A and DAG in nodular PWS lesions. Our data showed that there is aberrant activation of PKCα, PI3K, PDPK1 and PLC-γ and upregulation of PP2A and DAG mainly in endothelial cells in hypertrophic PWS areas, but presenting in the entire vasculatures and surrounding fibroblasts in PWS nodules. Our data suggest that both PKCα and PI3K signaling pathways contribute to the development of hypertrophy and nodularity in adult PWS.

Highlights

Port wine stain (PWS) is a congenital, progressive vascular malformation of human skin involving the superficialFrom the *Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China; †Departments of Dermatology, The Second Clinical Medical College, Shanxi Medical University, Taiyuan, China; ‡Department of Surgery, Beckman Laser Institute and Medical Clinic, University of California, Irvine, CA; and §Department of Biomedical Engineering, University of California, Irvine, CA.Supported by National Natural Scientific Foundation of China (81301355 to LG, 81430073 and 81220108016 to GW), and NIH AR063766 to WT.R
Typical pathological features of vascular anomalies were observed in a series of biopsies from adjacent normal skin to Epitope p-phosphatidylinositol 3-kinases (PI3K) p-protein kinase C alpha (PKCa) p-phospholipase C g subunit (PLC-g) p-phosphoinositide-dependent protein kinase-1 (PDPK1) phosphatase 2a (PP2A) DAG
One is a lack of nerve innervation to blood vessels contributing to development of PWS; the other is genetic mutations causing PWS, which is favored by many researchers

Summary

INTRODUCTION

Port wine stain (PWS) is a congenital, progressive vascular malformation of human skin involving the superficial. PWS are flat red macules, but lesions tend to darken progressively to purple and, by middle age, often become raised as a result of the development of vascular nodules.[7,8] The late-stage cobblestoning appearance of PWS subjects is comprised by pronounced vascular ectasia with proliferation of thin and/or thick-walled vessels and their stroma, and numerous epithelial, neural and mesenchymal hamartomatous abnormalities.[9] Despite these histologic observations, the specific mechanisms involved in PWS nodular formation remains unclear. B (AKT) and phosphoinositide phospholipase C g subunit (PLC-g) were activated in both hypertrophic areas and nodules within the lesion.[10] These observations led us to hypothesize that the PI3K pathway may play an important role in nodular formation. We attempt to further investigate the phosphorylation levels of various kinases involved in the PI3K pathway, including 3-phosphoinositide-dependent protein kinase-1 (PDPK1), protein kinase C alpha (PKCa), protein phosphatase 2a (PP2A), PI3K, 1,2-Diacylglycerol (DAG) and PLC-g, in hypertrophic and nodular PWS lesions

MATERIALS AND METHODS

RESULTS

DISCUSSION