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 #
5R01HL094567-04
Application #
8269023
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Gao, Yunling
Project Start
2009-07-22
Project End
2013-06-30
Budget Start
2012-06-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$392,361
Indirect Cost
$105,449
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Mentzer, Steven J; Konerding, Moritz A (2014) Intussusceptive angiogenesis: expansion and remodeling of microvascular networks. Angiogenesis 17:499-509
Belle, Janeil; Ysasi, Alexandra; Bennett, Robert D et al. (2014) Stretch-induced intussuceptive and sprouting angiogenesis in the chick chorioallantoic membrane. Microvasc Res 95:60-7
Filipovic, Nenad; Gibney, Barry C; Nikolic, Dalibor et al. (2014) Computational analysis of lung deformation after murine pneumonectomy. Comput Methods Biomech Biomed Engin 17:838-44
Ackermann, Maximilian; Tsuda, Akira; Secomb, Timothy W et al. (2013) Intussusceptive remodeling of vascular branch angles in chemically-induced murine colitis. Microvasc Res 87:75-82
Ysasi, Alexandra B; Belle, Janeil M; Gibney, Barry C et al. (2013) Effect of unilateral diaphragmatic paralysis on postpneumonectomy lung growth. Am J Physiol Lung Cell Mol Physiol 305:L439-45
Filipovic, Nenad; Gibney, Barry C; Kojic, Milos et al. (2013) Mapping cyclic stretch in the postpneumonectomy murine lung. J Appl Physiol (1985) 115:1370-8
Chamoto, Kenji; Gibney, Barry C; Lee, Grace S et al. (2013) Migration of CD11b+ accessory cells during murine lung regeneration. Stem Cell Res 10:267-77
Chamoto, Kenji; Gibney, Barry C; Ackermann, Maximilian et al. (2013) Alveolar epithelial dynamics in postpneumonectomy lung growth. Anat Rec (Hoboken) 296:495-503
Chamoto, Kenji; Gibney, Barry C; Ackermann, Maximilian et al. (2012) Alveolar macrophage dynamics in murine lung regeneration. J Cell Physiol 227:3208-15
Gibney, Barry C; Chamoto, Kenji; Lee, Grace S et al. (2012) Cross-circulation and cell distribution kinetics in parabiotic mice. J Cell Physiol 227:821-8

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