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Biology 624 - Developmental Genetics

Biology 624 - Developmental Genetics. Lecture #9 -Blood Vessel Formation. Blood vessel formation is important in: Embryogenesis Pregnancy Wound healing Disease. Tumor vascularization is a major step in tumor progression.

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Biology 624 - Developmental Genetics

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  1. Biology 624 - Developmental Genetics Lecture #9 -Blood Vessel Formation

  2. Blood vessel formation is important in: Embryogenesis Pregnancy Wound healing Disease

  3. Tumor vascularization is a major step in tumor progression

  4. Diabetic retinopathy (excess blood vessels in the eye) is a major cause of blindness

  5. VEGF Signaling Pathway FromShibuya, 2006

  6. Cell Division + Migration + Survival + Cell Division - Migration + VEGF Signaling Pathway VEGF Flk-1 Flk-1 Flt-1 VEGF Angioblast Endothelial Cell

  7. ES cell mutant vascular phenotype mimics mutant phenotype in vivo Wild-type Flk-1-/- Flt-1-/-

  8. angioblasts Vascular development - differentiation of angioblasts Mesoderm Hemangioblast Hematopoietic cells

  9. Embryonic vascular differentiation via the hemangioblast

  10. angioblasts Vascular development - differentiation of angioblasts Mesoderm Hemangioblast Hematopoietic cells

  11. Single cell fate mapping in fish gives Evidence for the hemangioblast FITC = descendants of single cell at 40% epiboly From Vogeli et al, 2006

  12. Circulatory System of a 4-Week Human Embyro

  13. angioblasts Embryonic vascular development Sprouting Angiogenesis Recruitment of mural cells and Remodeling Vasculogenesis proliferation migration VSMCs/pericytes differentiation assembly primitive vessel mature blood vessel branching vascular plexus

  14. angioblasts Vasculogenesis VEGF bFGF differentiation assembly primitive vessel

  15. Angiogenesis VEGF/neuropilin Slit/robo Netrin/unc Ephrin/eph Notch/delta proliferation migration sprouting branching vascular plexus primitive vessel

  16. Retinal angiogenesis occurs outward from optic nerve postnatally From Gerhardt et al, 2003

  17. Tip cell vs. stalk cell Tip cell: Does not proliferate Extends numerous filopodia Expresses markers- VEGFR2, PDGFB, Dll4, etc Stalk cell: Proliferates Has few filopodia Down-reglates tip cell markers From Gerhardt et al, 2003

  18. From Gerhardt et al, 2003 Tip cell characteristics Express PDGFB No proliferation Actin-rich filopodia

  19. VEGF pathway influences tip cells From Gerhardt et al, 2003

  20. Cell Division + Migration + Survival + Cell Division - Migration + VEGF Signaling Pathway VEGF Flk-1 Flk-1 Flt-1 VEGF Angioblast Endothelial Cell Soluble flt-1 isoform selectively rescues migration/branching

  21. Emerging flt-1 mutant sprouts differ from WT sprouts Local sprout guidance measures are rescued by sFlt-1 but not mFlt-1 Chappell et al. (2009) Dev Cell 17, 377

  22. Local sprout guidance measures are perturbedIn retinas with reduced Flt-1 activity Flt-1 neutr ab flt-1flox/flox Adeno-Cre flt-1flox/flox flt-1flox/flox Chappell et al. (2009) Dev Cell 17, 377

  23. Day 0 flt-1-/- ES cells Wild-type ES cells “Hanging drop” EBs Day 8 Mosaic blood vessels 1:1

  24. Local sprout guidance measures are rescued by sFlt-1 but not mFlt-1 in lateral base areas Chappell et al. (2009) Dev Cell 17, 377

  25. Local Sprout Guidance -- “pushes” the nascent sprout away from parent vessel -- utilizes soluble Flt-1 generated by parent vessel

  26. Lumen formation in developingblood vessels HUVEC Zebrafish Kamei et al, 2006

  27. Discontinuous lumens form and then connect in developingblood vessels Kamei et al, 2006

  28. Intersomitic vessels appear composed of 4-7 cells and intercellular junctions Mosaic analysis Junction marker stain Blum et al, 2008

  29. Putative structure of zebrafish intersomitic vessels Blum et al, 2008

  30. The mouse DA forms via Cord Hollowing Strilic et al, 2009

  31. Guidance pathways in vascular development From Klagsbrun and Eichmann, 2005

  32. Remodeling Ang PDGF Recruitment of Smooth muscle /pericytes branching vascular plexus mature blood vessel

  33. Ephrin/Eph specifies arteries vs. veins

  34. A-V formation in fish requires Vegfa Saggital sections of zebrafish over time show that Vegfa knockdown enhances CV formation at the expense of DA Herbert et al, 2009, Science Transverse sections show that Vegfa perturbations enhance CV formation at the expense of DA, while opposite for PI3K inh.

  35. Blocking flow down-regulates arterial markers and up-regulates venous markers From le Noble et al, 2004

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