Local regulation of angiogenesis by microenvironment

$301,530R01FY2007EBNIH

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Paper 39221109 Paper 38911024 Paper 38693998 Paper 37808725 Paper 35763565 Paper 34878922 Paper 33776613 Paper 33613149 Paper 33511324 Paper 33453155 Paper 32632100 Paper 32320015 Paper 32051585 Paper 31489365 Paper 31318321 Paper 30953042 Paper 29625073 Paper 29570992 Paper 29515935 Paper 29499152 Paper 29170549 Paper 29160307 Paper 29093558 Paper 28851858 Paper 28765370 Paper 28724577 Paper 28376260 Paper 28292428 Paper 28263185 Paper 28062569 Paper 27721906 Paper 27637342 Paper 27589843 Paper 27570735 Paper 27209346 Paper 27123817 Paper 26980715 Paper 26461445 Paper 26122846 Paper 25851120 Paper 25390971 Paper 25306545 Paper 25269668 Paper 24843171 Paper 24439276 Paper 24401172 Paper 24395588 Paper 24010014 Paper 23814115 Paper 23787488 Paper 23730348 Paper 23716647 Paper 23672518 Paper 23611564 Paper 23610423 Paper 23569284 Paper 23537666 Paper 23395612 Paper 23277584 Paper 23063436 Paper 23057744 Paper 22976544 Paper 22797912 Paper 22751181 Paper 22404680 Paper 22331826 Paper 22238361 Paper 21967638 Paper 21763607 Paper 21640103 Paper 21445393 Paper 21356349 Paper 21354386 Paper 21298148 Paper 21293460 Paper 21076420 Paper 20976722 Paper 20965727 Paper 20886900 Paper 20862208 Paper 20682635 Paper 20676108 Paper 20463286 Paper 20180698 Paper 20138664 Paper 20082286 Paper 19570510 Paper 19541627 Paper 19258396 Paper 19247618 Paper 19197330 Paper 18703661 Paper 18652824 Paper 18447536 Paper 17884241 Paper 17712140 Paper 17673200 Paper 17613314 Paper 16847103 Paper 16708468

Abstract

DESCRIPTION (provided by applicant): The vascularization of engineered tissues is critical to the ultimate success of tissue engineering as an organ replacement therapy. The formation of new capillary vessels in vivo, or angiogenesis, is linked to the pathogenesis of numerous diseases including cancer, and is regulated by local cues within the tissue microenvironment. The general goal of this RENEWAL proposal is to understand the mechanism by which local extracellular matrix (ECM) properties regulate capillary endothelial cell proliferation and capillary tube morphogenesis required in angiogenesis. The investigator has found that adhesion to ECM cooperates with growth factors to generate not only biochemical, but also mechanical signals that are important to driving capillary endothelial cell function. Studies from the past grant period demonstrated that the spatial organization and geometric presentation of ECM affects the degree to which cells attach and spread against the substrate. These changes in cell shape regulated proliferation and capillary tube formation by modulating contractile tension generated by the actin cytoskeleton. It was also found that changes in the mechanical stiffness of the ECM also regulated proliferation and tubulogenesis, likely by modulating similar mechanical signals. In this proposal, the investigator proposes to further investigate the role of these structural and mechanical cues in regulating angiogenic behaviors. Specific Aim 1 will be to investigate the cooperation between ECM geometry, soluble factors, and cell mechanics in regulating capillary growth and differentiation. Specific Aim 2 will be to investigate the role of ECM stiffness in regulating cell shape, mechanics, and EC function. Specific Aim 3 will be to examine the role of mechanical cues in regulating angiogenic responses in 3-dimensional tissue microenvironments. Together, these studies will define the mechanisms by which local structural and mechanical properties within ECM modulate cell function and capillary morphogenesis, and establish new strategies to promote angiogenesis in native ischemic tissues as well as in ex-vivo engineered tissues.

View original record on NIH RePORTER →