Cardiomyocyte hypertrophy and degradation of connexin43 through spatially restricted autocrine/paracrine heparin-binding EGF.
Growth factor signaling can affect tissue remodeling through autocrine/paracrine mechanisms. Recent evidence indicates that EGF receptor transactivation by heparin-binding EGF (HB-EGF) contributes to hypertrophic signaling in cardiomyocytes. Here, we show that HB-EGF operates in a spatially restricted circuit in the extracellular space within the myocardium, revealing the critical nature of the local microenvironment in intercellular signaling. This highly localized microenvironment of HB-EGF signaling was demonstrated with 3D morphology, consistent with predictions from a computational model of EGF signaling. HB-EGF secretion by a given cardiomyocyte in mouse left ventricles led to cellular hypertrophy and reduced expression of connexin43 in the overexpressing cell and in immediately adjacent cells but not in cells farther away. Thus, HB-EGF acts as an autocrine and local paracrine cardiac growth factor that leads to loss of gap junction proteins within a spatially confined microenvironment. These findings demonstrate how cells can coordinate remodeling with their immediate neighboring cells with highly localized extracellular EGF signaling.
Yoshioka
Jun
J
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA.
Prince
Robin N
RN
Huang
Hayden
H
Perkins
Scott B
SB
Cruz
Francisco U
FU
MacGillivray
Catherine
C
Lauffenburger
Douglas A
DA
Lee
Richard T
RT
D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D018031:Connexin 43 / Q000378:metabolism*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D018014:Gene Transfer Techniques; D006493:Heparin / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D007150:Immunohistochemistry; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000502:physiology*
D018031:Connexin 43; D017931:DNA Primers; D004815:Epidermal Growth Factor; D006493:Heparin; D066246:ErbB Receptors