Understanding the mechanisms by which endothelial cells (ECs) coordinate vascular growth and maintenance has been essential in efforts to modulate EC function in disease states. ECs interact with the ECM through integrin adhesion receptors which are required for EC migration and proliferation. The upregulation of integrin affinity for extracellular ligands, integrin activation, depends on the binding of talin, a cytoskeletal adaptor, to the bintegrin tail. EC talin1 is essential for embryonic angiogenesis in mice. Here, I utilized inducible, EC-specific murine models to delete talin1 or induce the expression of an integrin-activation deficient mutant, talin1 L325R to investigate the role of talin and talin-dependent integrin activation in postnatal angiogenesis and in the maintenance of established vessels.
Inducible deletion of talin1 during early postnatal development resulted in vascular hemorrhage, impaired angiogenesis and lethality. Expression of talin1 L325R in ECs during postnatal development impaired retinal angiogenesis but lethality or vascular hemorrhage were not observed in Tln1 L325R mice. However, Tln1 L325R mice were smaller at weaning and throughout adulthood. Interestingly, subcutaneous B16-F0 melanomas grew more slowly in Tln1 L325R mice and showed a marked reduction in tumor angiogenesis. These data indicate that talin-dependent integrin activation is indispensable for postnatal developmental and pathological angiogenesis.
To investigate the role of talin expression in established blood vessels, EC talin deletion was induced in adult mice. EC talin1 deletion caused death 16-20 days after deletion associated with leaky intestinal vasculature. Intestinal ECs of Tln1 EC-KO mice formed cyst-like structures that were detached from neighboring cells with disorganized adherens junctions. Tln1 deletion in cultured ECs promoted cytoskeletal contraction, adherens junction disorganization and diminished barrier function. Genetic and pharmacological experiments suggested that talin was functioning to maintain barrier function primarily by activating B1 integrin.
These results provide important novel insights into how EC integrin activation contributes to blood vessel development and integrity. Future studies building upon this work should reveal new strategies to therapeutically target integrin signaling in order to modulate blood vessel growth and EC barrier function.
Table of Contents
Chapter 1. Introduction
1.1 Development of the Cardiovascular System
1.1.1 Vascular Structure, Organization and Physiological Function
1.1.2 Regulation of New Blood Vessel Growth
1.1.3 Vascular Homeostasis and Barrier Function
1.2 Endothelial Cell Adhesion in Disease
1.2.1 Dysregulation of EC Adhesion in Cancer
1.2.2 Dysregulation of Cell-Cell Adhesion in Conditions of Hyperpermeability
1.3 The Role of Integrins in Endothelial Cell Function
1.3.1 Integrin Adhesion and Signaling
1.3.2 Integrin Signaling and Function in Angiogenesis
1.3.3 Integrin Signaling and Function in Vascular Permeability
1.4 Talin: Master Regulator of Integrin Activation
1.4.1 Mechanism of Talin-Mediated Integrin Activation
1.4.2 The Role of Talin in Blood Cells
1.4.3 The Role of Talin Function in ECs
1.5 Dissertation Goals
Chapter 2. Endothelial Cell Talin-dependent Integrin Activation is Required for Postnatal Angiogenesis
Chapter 3. Talin-Dependent Integrin Activations Regulates VE-cadherin Localization and Endothelial Cell Barrier Function
Chapter 4: Discussion and Future Directions
4.1 The Role of EC talin1 in Postnatal Angiogenesis
4.2 The Role of EC Talin1 in the Regulation of Barrier Function in Established Vessels
4.3 Future Directions
About this Dissertation
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