Extracellular matrix density regulates the rate of neovessel growth and branching in sprouting angiogenesis.
Angiogenesis is regulated by the local microenvironment, including the mechanical interactions between neovessel sprouts and the extracellular matrix (ECM). However, the mechanisms controlling the relationship of mechanical and biophysical properties of the ECM to neovessel growth during sprouting angiogenesis are just beginning to be understood. In this research, we characterized the relationship between matrix density and microvascular topology in an in vitro 3D organ culture model of sprouting angiogenesis. We used these results to design and calibrate a computational growth model to demonstrate how changes in individual neovessel behavior produce the changes in vascular topology that were observed experimentally. Vascularized gels with higher collagen densities produced neovasculatures with shorter vessel lengths, less branch points, and reduced network interconnectivity. The computational model was able to predict these experimental results by scaling the rates of neovessel growth and branching according to local matrix density. As a final demonstration of utility of the modeling framework, we used our growth model to predict several scenarios of practical interest that could not be investigated experimentally using the organ culture model. Increasing the density of the ECM significantly reduced angiogenesis and network formation within a 3D organ culture model of angiogenesis. Increasing the density of the matrix increases the stiffness of the ECM, changing how neovessels are able to deform and remodel their surroundings. The computational framework outlined in this study was capable of predicting this observed experimental behavior by adjusting neovessel growth rate and branching probability according to local ECM density, demonstrating that altering the stiffness of the ECM via increasing matrix density affects neovessel behavior, thereby regulated vascular topology during angiogenesis.
Department of Bioengineering, University of Utah, Salt Lake City, Utah, United States of America ; Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah, United States of America.
Lowell T
LT
Edgar
Department of Bioengineering, University of Utah, Salt Lake City, Utah, United States of America ; Medical Products Division, W.L. Gore and Associates, Inc., Flagstaff, Arizona, United States of America.
Clayton J
CJ
Underwood
Department of Mechanical Engineering, University of Utah, Salt Lake City, Utah, United States of America.
James E
JE
Guilkey
Division of Cardiovascular Therapeutics, Cardiovascular Innovation Institute, University of Louisville, Kentucky, United States of America.
James B
JB
Hoying
Department of Bioengineering, University of Utah, Salt Lake City, Utah, United States of America ; Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah, United States of America.
Jeffrey A
JA
Weiss
D000465:Algorithms; D000818:Animals; D003094:Collagen / Q000378:metabolism / Q000502:physiology; D003198:Computer Simulation; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology*; D008297:Male; D018613:Microscopy, Confocal; D008858:Microscopy, Phase-Contrast; D055806:Microvessels / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D008954:Models, Biological; D009024:Morphogenesis; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D042461:Vascular Endothelial Growth Factor A; D003094:Collagen