PMID- 12391106
OWN - NLM
STAT- MEDLINE
DCOM- 20030512
LR  - 20220321
IS  - 8750-7587 (Print)
IS  - 0161-7567 (Linking)
VI  - 93
IP  - 6
DP  - 2002 Dec
TI  - Pulmonary hypertension in TNF-alpha-overexpressing mice is associated with 
      decreased VEGF gene expression.
PG  - 2162-70
AB  - Tumor necrosis factor-alpha (TNF-alpha) transgenic mice have previously been 
      found to have characteristics consistent with emphysema and severe pulmonary 
      hypertension. Lungs demonstrated alveolar enlargement as well as interstitial 
      thickening due to chronic inflammation and perivascular fibrosis. In the present 
      report, we sought to determine potential mechanisms leading to development of 
      pulmonary hypertension in TNF-alpha transgenic mice. To determine whether 
      sustained vasoconstriction was an important component of this pulmonary 
      hypertension, nitric oxide was administered and hemodynamics were measured. 
      Nitric oxide (25 ppm) failed to normalize right ventricular pressure in 
      transgene-positive mice, suggesting that the pulmonary hypertension was not due 
      to sustained vasoconstriction. Structural analysis of the pulmonary arteries 
      found adventitial thickening and a trend toward medial hypertrophy in pulmonary 
      arteries of transgene-positive mice, suggesting that vascular remodeling had 
      occurred. Echocardiographic measurement of the percent fractional shortening of 
      the left ventricle as a measurement of ventricular function in vivo revealed that 
      left ventricular dysfunction was not contributing to pulmonary hypertension. We 
      examined expression of genes known to be important in regulation of vascular tone 
      and structure. Messenger RNA expression of vascular endothelial growth factor and 
      its receptor flk-1 was reduced compared with transgene-negative littermates at 
      all ages. Endothelial and inducible nitric oxide synthase mRNA levels were 
      similar in both groups. Endothelin-1 mRNA was also decreased in TNF-alpha 
      transgenic mice. Interestingly, female transgenic mice had decreased survival 
      rate compared with male transgenic mice. We conclude that chronic overexpression 
      of TNF-alpha is associated with decreased vascular endothelial growth factor and 
      flk-1 gene expression, pulmonary vascular remodeling, and severe pulmonary 
      hypertension, although the precise mechanism is unknown.
FAU - Fujita, Masaki
AU  - Fujita M
AD  - Research Institute for Disease of the Chest, Graduate School of Medical Sciences, 
      Kyushu University, Fukuoka 812-8582 Japan.
FAU - Mason, Robert J
AU  - Mason RJ
FAU - Cool, Carleyne
AU  - Cool C
FAU - Shannon, John M
AU  - Shannon JM
FAU - Hara, Nobuyuki
AU  - Hara N
FAU - Fagan, Karen A
AU  - Fagan KA
LA  - eng
GR  - HL-56556/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20020809
PL  - United States
TA  - J Appl Physiol (1985)
JT  - Journal of applied physiology (Bethesda, Md. : 1985)
JID - 8502536
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lymphokines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
SB  - IM
MH  - Animals
MH  - Echocardiography
MH  - Endothelial Growth Factors/*genetics
MH  - Female
MH  - Gene Expression/physiology
MH  - Hypertension, Pulmonary/mortality/pathology/*physiopathology
MH  - Intercellular Signaling Peptides and Proteins/*genetics
MH  - Lung/blood supply/pathology/physiopathology
MH  - Lymphokines/*genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Nitric Oxide/pharmacology
MH  - RNA, Messenger/analysis
MH  - Survival Rate
MH  - Tumor Necrosis Factor-alpha/*genetics
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factor Receptor-2/genetics
MH  - Vascular Endothelial Growth Factors
MH  - Ventricular Dysfunction, Left/diagnostic imaging/physiopathology
EDAT- 2002/10/23 04:00
MHDA- 2003/05/13 05:00
CRDT- 2002/10/23 04:00
PHST- 2002/10/23 04:00 [pubmed]
PHST- 2003/05/13 05:00 [medline]
PHST- 2002/10/23 04:00 [entrez]
AID - 00083.2002 [pii]
AID - 10.1152/japplphysiol.00083.2002 [doi]
PST - ppublish
SO  - J Appl Physiol (1985). 2002 Dec;93(6):2162-70. doi: 
      10.1152/japplphysiol.00083.2002. Epub 2002 Aug 9.