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

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Presentation on theme: "Biology 624 - Developmental Genetics Lecture #9 -Blood Vessel Formation."— Presentation transcript:

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

2 Blood vessel formation is important in: 1.Embryogenesis 2.Pregnancy 3.Wound healing 4.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 VEGF Flk-1 Angioblast Flk-1Flt-1 VEGF VEGF Signaling Pathway Cell Division + Migration + Survival + Cell Division - Migration + Endothelial Cell

7 ES cell mutant vascular phenotype mimics mutant phenotype in vivo Wild-typeFlk-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 From Vogeli et al, 2006 FITC = descendants of single cell at 40% epiboly

12 Circulatory System of a 4-Week Human Embyro

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

14 angioblasts primitive vessel differentiation assembly Vasculogenesis VEGFbFGF

15 branching vascular plexus primitive vessel proliferation migration sprouting Angiogenesis VEGF/neuropilinSlit/roboNetrin/uncEphrin/ephNotch/delta

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

17 From Gerhardt et al, 2003 Tip cell vs. stalk cell Tip cell: 1. Does not proliferate 2. Extends numerous filopodia 3. Expresses markers- VEGFR2, PDGFB, Dll4, etc Stalk cell: 1. Proliferates 2. Has few filopodia 3. Down-reglates tip cell markers

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

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

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

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

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

23 Wild-type ES cells flt-1-/- ES cells Day 8 Day 0 Mosaic blood vessels “Hanging drop” EBs 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 Local Sprout Guidance -- “pushes” the nascent sprout away from parent vessel -- utilizes soluble Flt-1 generated by parent vessel

26 Lumen formation in developing blood vessels Kamei et al, 2006 HUVECZebrafish

27 Discontinuous lumens form and then connect in developing blood vessels Kamei et al, 2006

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

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

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

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

32 branching vascular plexus Recruitment of Smooth muscle /pericytes mature blood vessel Remodeling AngPDGF

33 Ephrin/Eph specifies arteries vs. veins

34 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. A-V formation in fish requires Vegfa

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

36


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