Small artery remodeling and erythrocyte deformability in L-NAME-induced hypertension: role of transglutaminases.
BACKGROUND
Hypertension is associated with inward remodeling of small arteries and decreased erythrocyte deformability, both impairing proper tissue perfusion. We hypothesized that these alterations depend on transglutaminases, cross-linking enzymes present in the vascular wall, monocytes/macrophages and erythrocytes.


RESULTS
Wild-type (WT) mice and tissue-type transglutaminase (tTG) knockout (KO) mice received the nitric oxide inhibitor Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME) to induce hypertension. After 1 week, mesenteric arteries from hypertensive WT mice showed a smaller lumen diameter (-6.9 +/- 2.0%, p = 0.024) and a larger wall-to-lumen ratio (11.8 +/- 3.5%, p = 0.012) than controls, whereas inward remodeling was absent in hypertensive tTG KO mice. After 3 weeks, the wall-to-lumen ratio was increased in WT (20.8 +/- 4.8%, p = 0.005) but less so in tTG KO mice (11.7 +/- 4.6%, p = 0.026), and wall stress was normalized in WT but not in tTG KO mice. L-NAME did not influence expression of tTG or an alternative transglutaminase, coagulation factor XIII (FXIII). Suppression of FXIII by macrophage depletion was associated with increased tTG in the presence of L-NAME. L-NAME treatment decreased erythrocyte deformability in the WT mice (-15.3% at 30 dynes/cm(2), p = 0.014) but not in the tTG KO mice.


CONCLUSIONS
Transglutaminases are involved in small artery inward remodeling and erythrocyte stiffening associated with nitric oxide inhibition-related hypertension.
Pistea
Adrian
A
Department of Medical Physics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Bakker
Erik N T P
EN
Spaan
Jos A E
JA
Hardeman
Max R
MR
van Rooijen
Nico
N
VanBavel
Ed
E
D000818:Animals; D001794:Blood Pressure; D004002:Clodronic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors; D004907:Erythrocyte Deformability; D005176:Factor XIII / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006400:Hematocrit; D006973:Hypertension / Q000097:blood / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008638:Mesenteric Arteries / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012107:Research Design; D013314:Stress, Mechanical; D013997:Time Factors; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004002:Clodronic Acid; D009569:Nitric Oxide; D005176:Factor XIII; D019001:Nitric Oxide Synthase; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D019331:NG-Nitroarginine Methyl Ester