Localized HB-EGF signaling and Connexin43 decrease in the myocardium

Growth factor signaling can affect tissue remodeling through autocrine and paracrine mechanisms. Recent evidence indicates that hypertrophic signaling in cardiomyocytes is induced through transactivation of the epidermal growth factor (EGF) receptor by heparin-binding EGF (HB-EGF). Here it is shown that HB-EGF operates in a spatially restricted local circuit in the extracellular space within the myocardium, revealing the critical nature of the local microenvironment in intercellular signaling. In vitro studies demonstrated that HB-EGF acts as an autocrine growth factor in cultures of rat neonatal cardiomyocytes. However, in vivo experiments in adult mouse left ventricles demonstrated that HB-EGF secretion by a given cardiomyocyte leads to cellular hypertrophy in cells overexpressing HB-EGF and in adjacent cells, but not in cells farther away. This highly localized microenvironment of HB-EGF signaling was also demonstrated using 3D morphology to assess cardiomyocyte growth and was predicted by a computational model of HB- EGF diffusion and binding in the myocardium. Additionally, in vitro and in vivo studies demonstrated that HB-EGF promotes loss of the principal ventricular gap junction protein Connexin43 (Cx43) in cardiomyocytes. 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 within the myocardium. This demonstration of localized intercellular signaling demonstrates how cells can coordinate remodeling with their immediate neighboring cells without affecting others nearby.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Mechanical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2005

Author dc:creator

• Prince, Robin Neely

Advisor dc:contributor.advisor

• Douglas A. Lauffenburger and Richard T. Lee.

• Mechanical Engineering.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/32346

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/32346