Adult Tissue Morphogenesis: Functinoal Regulation of Intussusceptive Antiogenesis

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): 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.