During developmental growth, tissue repair and disease the vasculature is remodelled and expanded through the process of angiogenesis to enhance oxygen and nutrient supply. Sprouting angiogenesis is the principal mechanism by which this occurs and takes place following the activation of endothelial cells (ECs) and surrounding pericytes by pro-angiogenic signals. Subsequent degradation of the basement membrane and invasion of ECs into the surrounding extracellular matrix leads to the formation of an angiogenic sprout that forms contacts with neighbouring vessels and undergoes lumen formation and stabilisation to produce a functional vessel through which blood can flow. This process requires dramatic changes in EC polarity and shape that is orchestrated by a highly dynamic cytoskeleton. Previous work from our lab identified the formin FMNL3 as an important regulator of sprouting angiogenesis. The mechanistic understanding of FMNL3s function in this process is however poorly understood. Through the use of in vitro assays of endothelial migration and polarity FMNL3 was found to be important for the reorientation of cell polarity during endothelial migration. Following the formation of an angiogenic sprout ECs need to become less invasive and reorient their polarity along their apical-basolateral axis to allow lumen formation. The function of FMNL3 in endothelial polarisation during migration led to the investigation of a role for FMNL3 in apical-basolateral polarisation. FMNL3 was found to be required for the localisation of the protein Podocalyxin-like 1 (PODXL) to the apical surface of ECs through the assembly and remodelling of endothelial apical actin filaments. This function of FMNL3 was found to occur downstream of RhoJ. PODXL associates with apical actin filaments and is transported along it through Myosin Vb and Rab25. PODXL is important for specification of the apical surface prior to lumen formation and this study identifies FMNL3 as an important protein in the localisation of PODXL to the apical membrane through regulation of the endothelial cytoskeleton.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:688216 |
| Date | January 2015 |
| Creators | Richards, Mark D. |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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