Histamine-modulated transdifferentiation of dermal microvascular endothelial cells.
Homeostatic and inflammatory functions of skin microvessels are tightly regulated by vasoactive amines. Following stimulation with histamine, dermal microvascular endothelial cells (MEC) undergo a rapid change in phenotype (transdifferentiation) and subsequently exhibit an enhanced rate of growth. To elucidate mechanisms regulating MEC transdifferentiation, this study investigated the functional relationships among vimentin, Ca2+, and protein kinase C (PKC) in histamine-modulated dermal MEC in vitro. Distribution of vimentin and PKC in foreskin-derived MEC cultivated in a modified Iscove's medium was assessed with immunocytochemistry. Calcium ion kinetics in histamine-treated MEC were analyzed using the Ca2+ probe Fluo-3 in conjunction with interactive laser cytometry. Histamine, acting through H-1 receptors, produces a rapid (less than 100 ms) and differential elevation of free calcium in each of three cytological compartments defined by the vimentin cytoskeleton in epithelial MEC. A distinctive compartmentalized and nonuniform distribution of PKC precisely coincides with that observed for free-Ca2+ released in response to histamine. The studies reveal that histamine modulation of the MEC phenotype is associated with a rapid patterned reorganization of the vimentin skeleton. It is hypothesized that histamine induces vimentin post-translational modifications by activating a spatially localized interaction among cytoplasmic free Ca2+, PKC, and the vimentin matrix. The results further suggest that vimentin, in addition to its structural role, may participate in signal transduction and gene regulation processes in effecting MEC transdifferentiation.
Lipton
B H
BH
Department of Dermatology, Stanford University School of Medicine, California 94305.
Bensch
K G
KG
Karasek
M A
MA
D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent; D002454:Cell Differentiation; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006632:Histamine / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D011493:Protein Kinase C / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D012867:Skin / Q000166:cytology* / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D002413:Cations, Divalent; D011968:Receptors, Histamine; D014746:Vimentin; D006632:Histamine; D011493:Protein Kinase C; D002118:Calcium