Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B-deficient mice.
The protein tyrosine phosphatase 1B (PTP1B) modulates tyrosine kinase receptors, among which is the vascular endothelial growth factor receptor type 2 (VEGFR2), a key component of angiogenesis. Because PTP1B deficiency in mice improves left ventricular (LV) function 2 mo after myocardial infarction (MI), we hypothesized that enhanced angiogenesis early after MI via activated VEGFR2 contributes to this improvement. At 3 d after MI, capillary density was increased at the infarct border of PTP1B(-/-) mice [+7±2% vs. wild-type (WT), P = 0.05]. This was associated with increased extracellular signal-regulated kinase 2 phosphorylation and VEGFR2 activation (i.e., phosphorylated-Src/Src/VEGFR2 and dissociation of endothelial VEGFR2/VE-cadherin), together with higher infiltration of proangiogenic M2 macrophages within unchanged overall infiltration. In vitro, we showed that PTP1B inhibition or silencing using RNA interference increased VEGF-induced migration and proliferation of mouse heart microvascular endothelial cells as well as fibroblast growth factor (FGF)-induced proliferation of rat aortic smooth muscle cells. At 8 d after MI in PTP1B(-/-) mice, increased LV capillary density (+21±3% vs. WT; P<0.05) and an increased number of small diameter arteries (15-50 μm) were likely to participate in increased LV perfusion assessed by magnetic resonance imaging and improved LV compliance, indicating reduced diastolic dysfunction. In conclusion, PTP1B deficiency reduces MI-induced heart failure promptly after ischemia by enhancing angiogenesis, myocardial perfusion, and diastolic function.
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
Marie
M
Besnier
INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris, France.
Ariane
A
Galaup
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
Lionel
L
Nicol
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
Jean-Paul
JP
Henry
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
David
D
Coquerel
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
Alexandre
A
Gueret
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
Paul
P
Mulder
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
Ebba
E
Brakenhielm
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
Christian
C
Thuillez
INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris, France.
Stéphane
S
Germain
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
Vincent
V
Richard
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and antoine.ouvrard-pascaud@univ-rouen.fr.
Antoine
A
Ouvrard-Pascaud
D000818:Animals; D001011:Aorta; D001160:Arterioles / Q000503:physiopathology; D002196:Capillaries / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000502:physiology*; D003971:Diastole; D042783:Endothelial Cells / Q000473:pathology; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology; D020257:Ventricular Remodeling
D002316:Cardiotonic Agents; D040301:Vascular Endothelial Growth Factor Receptor-2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
cytokines; growth factors; vascular growth