title: Role of rat alpha adducin in angiogenesis: null effect of the F316Y polymorphism.
abstract: OBJECTIVE
  Rat alpha adducin point mutation (F316Y) has been associated with primary systemic arterial hypertension. As microcirculatory abnormalities are present in most forms of hypertension, the aim of the present study was to investigate whether rat alpha adducin may regulate endothelial cell (EC) functions in vitro and in vivo.
  
  
  RESULTS
  The overexpression of rat wild type alpha adducin (WT-Add1) in ECs induced capillary-like structure development in Matrigel in vitro and enhanced capillary formation in Matrigel implants in vivo in CD1 mice. In contrast, the overexpression of the mutated form (MUT-Add1) of rat alpha adducin had a Null effect in vitro and lacked any significant activity in vivo. Further, adenovirus-mediated rat WT-Add1 but not MUT-Add1 gene transfer to murine ischemic hindlimb enhanced capillary formation in skeletal muscles. Gene profiling of human umbilical vein endothelial cells overexpressing alpha adducin was performed in order to identify putative effector molecules of alpha adducin-mediated activities on ECs. Interestingly, among a number of genes involved in angiogenesis regulation, retinoic acid-induced protein (RAI17) was found to be upregulated in WT-Add1 vs MUT-Add1 overexpressing cells, possibly representing a key molecule/axis for the functional Add1-induced effect.
  
  
  CONCLUSIONS
  Rat WT alpha adducin enhanced EC functions both in vitro and in vivo. The expression of the F316Y variant, associated with the hypertensive phenotype, had a Null effect and might contribute to endothelial rarefaction/dysfunction in hypertension. RAI17 was found to be a putative effector molecule differentially regulated by the overexpression of the two forms of Add1 in endothelial cells.
authors.affiliation: Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata-IRCCS, Via Monti di Creta 104, 00167, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cappuzzello
authors.forename: Roberta
authors.initials: R
authors.lastname: Melchionna
authors.forename: Antonella
authors.initials: A
authors.lastname: Mangoni
authors.forename: Grazia
authors.initials: G
authors.lastname: Tripodi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
authors.forename: Lucia
authors.initials: L
authors.lastname: Torielli
authors.forename: Diego
authors.initials: D
authors.lastname: Arcelli
authors.forename: Mauro
authors.initials: M
authors.lastname: Helmer-Citterich
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bianchi
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.forename: Monica
authors.initials: M
authors.lastname: Napolitano
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D005787:Gene Frequency; D006614:Hindlimb; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism; D007797:Laminin; D051379:Mice; D008815:Mice, Inbred Strains; D018919:Neovascularization, Physiologic / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D011509:Proteoglycans; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D000099291:Adducins
chemical_list: D002148:Calmodulin-Binding Proteins; D003094:Collagen; D004338:Drug Combinations; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D011509:Proteoglycans; D014157:Transcription Factors; D000099291:Adducins; C480599:ZMIZ1 protein, human; C059485:matrigel