PMID- 17693481
OWN - NLM
STAT- MEDLINE
DCOM- 20071127
LR  - 20211203
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 293
IP  - 4
DP  - 2007 Oct
TI  - Angiogenesis is induced by airway smooth muscle strain.
PG  - L1059-68
AB  - Angiogenesis is an important feature of airway remodeling in both chronic asthma 
      and chronic obstructive pulmonary disease (COPD). Airways in those conditions are 
      exposed to excessive mechanical strain during periods of acute exacerbations. We 
      recently reported that mechanical strain of human airway smooth muscle (HASM) led 
      to an increase in their proliferation and migration. Sustained growth in airway 
      smooth muscle in vivo requires an increase in the nutritional supply to these 
      muscles, hence angiogenesis. In this study, we examined the hypothesis that 
      cyclic mechanical strain of HASM produces factors promoting angiogenic events in 
      the surrounding vascular endothelial cells. Our results show: 1) a significant 
      increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, 
      migration, and tube formation following incubation in conditioned media (CM) from 
      HASM cells exposed to mechanical strain; 2) mechanical strain of HASM cells 
      induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited 
      the proliferation, migration, and tube formations of HMVEC-L induced by the 
      strained airway smooth muscle CM; 4) mechanical strain of HASM induced a 
      significant increase in hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and 
      protein, a transcription factor required for VEGF gene transcription; and 5) 
      mechanical strain of HASM induced HIF-1alpha/VEGF through dual 
      phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and 
      ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces 
      signal transduction pathway through PI3K/Akt/mTOR and ERK pathways that lead to 
      an increase in HIF-1alpha, a transcription factor required for VEGF expression. 
      VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen 
      with repeated exacerbation of asthma and COPD.
FAU - Hasaneen, Nadia A
AU  - Hasaneen NA
AD  - The Department of Medicine and Research, Veterans Affairs Medical Center, 
      Northport, New York, USA. Hussein.Foda@med.va.gov
FAU - Zucker, Stanley
AU  - Zucker S
FAU - Lin, Richard Z
AU  - Lin RZ
FAU - Vaday, Gayle G
AU  - Vaday GG
FAU - Panettieri, Reynold A
AU  - Panettieri RA
FAU - Foda, Hussein D
AU  - Foda HD
LA  - eng
GR  - R01 DK062722/DK/NIDDK NIH HHS/United States
GR  - CA-79866/CA/NCI NIH HHS/United States
GR  - DK-62722/DK/NIDDK NIH HHS/United States
GR  - HL-646340/HL/NHLBI NIH HHS/United States
GR  - R01 HL064340/HL/NHLBI NIH HHS/United States
GR  - R01 CA079866/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20070810
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (Antibodies)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Antibodies/pharmacology
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis
MH  - Lung/blood supply
MH  - Muscle, Smooth, Vascular/metabolism/*physiology
MH  - Myocytes, Smooth Muscle/metabolism/*physiology
MH  - *Neovascularization, Physiologic/drug effects
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction/physiology
MH  - Stress, Mechanical
MH  - TOR Serine-Threonine Kinases
MH  - Vascular Endothelial Growth Factor A/immunology/metabolism
EDAT- 2007/08/19 09:00
MHDA- 2007/12/06 09:00
CRDT- 2007/08/19 09:00
PHST- 2007/08/19 09:00 [pubmed]
PHST- 2007/12/06 09:00 [medline]
PHST- 2007/08/19 09:00 [entrez]
AID - 00480.2006 [pii]
AID - 10.1152/ajplung.00480.2006 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L1059-68. doi: 
      10.1152/ajplung.00480.2006. Epub 2007 Aug 10.