Inflammation-induced angiogenesis is a fundamental biologic process relevant to chronic inflammatory diseases, wound healing and tissue engineering. In these settings, a process that could rapidly expand capillary density would be of fundamental importance. To address this need, we have developed a murine colon model in which chemically-induced inflammation triggers intussusceptive (nonsprouting) angiogenesis. Previously considered a developmental phenomenon, intussusceptive angiogenesis is an underappreciated process in adult organs. Intussusceptive angiogenesis can rapidly expand capillary networks by the active subdivision of one vessel into two lumens. In our adult colon model, the earliest stage of intussusceptive angiogenesis is the formation of intraluminal """"""""pillars."""""""" Demonstrated by corrosion casting and 3-dimensional scanning electron microscopy (SEM), the pillars form within 7 days after chemical exposure. SEM demonstrates that the pillars are nonrandomly distributed at vessel junctions within the colon mucosal plexus. Over the next 3 weeks, the physical extension of the pillar down the luminal axis of the vessel results in capillary replication. Intravital microscopy of the mucosal plexus during this period demonstrates perturbed blood flow patterns including focally increased volumetric flow and oscillating flow. Our hypothesis is that these intravascular flow fields regulate the process of intussusceptive angiogenesis. Our long-term goal is to understand the dynamic interaction between intravascular blood flow and the molecular regulation of intussusceptive angiogenesis. To test our hypothesis, we have developed a multidisciplinary approach that integrates structural anatomy, intravital microscopy and computation flow modeling.
Our specific aims will test the hypothesis using the following approach: 1) Measure microvessel structure and blood flow patterns in the inflamed mucosal plexus;2) Model blood flow patterns during intussusceptive angiogenesis using computational flow simulations;3) Map gene expression within the mucosal plexus using laser capture microdissection. The long-term goal of this project is an understanding of the dynamic interaction between intravascular blood flow and the molecular regulation of intussusceptive angiogenesis.

Public Health Relevance

This project investigates the regulation of intussusceptive angiogenesis-a process of blood vessel replication that rapidly expands pre-existing vascular networks. The development of techniques and methods that can rapidly expand blood supply to injured tissue will have a significant impact on regenerative medicine and tissue engineering.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL094567-01A1
Application #
7736283
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Goldman, Stephen
Project Start
2009-07-22
Project End
2013-05-31
Budget Start
2009-07-22
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$433,547
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Servais, Andrew B; Kienzle, Arne; Ysasi, Alexandra B et al. (2018) Structural heteropolysaccharides as air-tight sealants of the human pleura. J Biomed Mater Res B Appl Biomater :
Kienzle, Arne; Servais, Andrew B; Ysasi, Alexandra B et al. (2018) Free-Floating Mesothelial Cells in Pleural Fluid After Lung Surgery. Front Med (Lausanne) 5:89
Haber, Shimon; Weisbord, Michal; Mentzer, Steven J et al. (2017) Alveolar septal patterning during compensatory lung growth: Part II the effect of parenchymal pressure gradients. J Theor Biol 421:168-178
Bennett, Robert D; Ysasi, Alexandra B; Wagner, Willi L et al. (2017) Deformation-induced transitional myofibroblasts contribute to compensatory lung growth. Am J Physiol Lung Cell Mol Physiol 312:L79-L88
Gibney, Barry C; Wagner, Willi L; Ysasi, Alexandra B et al. (2017) Structural and functional evidence for the scaffolding effect of alveolar blood vessels. Exp Lung Res 43:337-346
Valenzuela, Cristian D; Wagner, Willi L; Bennett, Robert D et al. (2017) Extracellular Assembly of the Elastin Cable Line Element in the Developing Lung. Anat Rec (Hoboken) 300:1670-1679
Haber, Shimon; Weisbord, Michal; Mishima, Michiaki et al. (2016) Interstitial fluid flow of alveolar primary septa after pneumonectomy. J Theor Biol 400:118-28
Henry, Frank S; Tsuda, Akira (2016) Onset of alveolar recirculation in the developing lungs and its consequence on nanoparticle deposition in the pulmonary acinus. J Appl Physiol (1985) 120:38-54
Tsuda, Akira; Venkata, Nagarjun Konduru (2016) The role of natural processes and surface energy of inhaled engineered nanoparticles on aggregation and corona formation. NanoImpact 2:38-44
Wagner, Willi; Bennett, Robert D; Ackermann, Maximilian et al. (2015) Elastin Cables Define the Axial Connective Tissue System in the Murine Lung. Anat Rec (Hoboken) 298:1960-8

Showing the most recent 10 out of 44 publications