title: Increased tyrosine phosphorylation mediates the cooling-induced contraction and increased vascular reactivity of Raynaud's disease.
abstract: OBJECTIVE
  Increased levels of protein tyrosine kinase (PTK) are mechanistically associated with increased contractile responsiveness to cooling. This study tests the hypothesis that increased PTK activity mediates the increased vascular reactivity to agonists and cooling associated with primary Raynaud's disease (RD).
  
  
  METHODS
  The response of dermal arterioles isolated from control (n = 29) and RD (n = 29) subjects to contractile and dilatory agents at 37 degrees C and 31 degrees C was characterized using the microvessel perfusion technique. Fluorescence immunohistochemistry was used to measure tyrosine phosphorylation.
  
  
  RESULTS
  At 37 degrees C, arteries from RD patients exhibited similar sensitivity to the specific alpha(2)-adrenergic agonist UK 14,304, to serotonin, and to angiotensin II. At 31 degrees C, however, the response to all 3 agonists was greater in the arterioles from the RD patients than in those from the control subjects. Agonist-induced contraction at both temperatures was reversed by cumulative addition of the PTK inhibitors genistein (1-30 microM) and tyrphostin 47 (0.1-10 microM). All arterioles from control subjects relaxed slightly in response to cooling, whereas more than half of those from RD patients contracted. This cooling-induced contraction was reversed by the cumulative addition of genistein. The 3 agonists elicited large increases in tyrosine phosphorylation only in arterial segments from RD patients at 31 degrees C. Cooling from 37 degrees C to 31 degrees C elicited a large increase in tyrosine phosphorylation in arterioles from RD patients, but not those from control subjects. All increases in tyrosine phosphorylation could be prevented by genistein.
  
  
  CONCLUSIONS
  Increased tyrosine phosphorylation mediates cooling-induced contraction and the increased vascular reactivity of skin arterioles from individuals with RD.
authors.affiliation: C.S. Mott Center, Wayne State University, 275 East Hancock Avenue, Detroit, MI 48201, USA. aa1985@wayne.edu
authors.forename: Philip B
authors.initials: PB
authors.lastname: Furspan
authors.forename: Soumya
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Robert R
authors.initials: RR
authors.lastname: Freedman
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage; D000328:Adult; D000804:Angiotensin II / Q000008:administration & dosage; D001160:Arterioles / Q000201:enzymology; D000068438:Brimonidine Tartrate; D003080:Cold Temperature; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D019833:Genistein / Q000008:administration & dosage; D006801:Humans; D008875:Middle Aged; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011810:Quinoxalines / Q000008:administration & dosage; D011928:Raynaud Disease / Q000378:metabolism* / Q000503:physiopathology; D012701:Serotonin / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000098:blood supply*; D012881:Skin Temperature; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000008:administration & dosage; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
chemical_list: D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D011810:Quinoxalines; D020032:Tyrphostins; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D012701:Serotonin; D014443:Tyrosine; D000068438:Brimonidine Tartrate; D019833:Genistein; D011505:Protein-Tyrosine Kinases