Comparison of blood and lymphatic vascular phenotypes in loss-of-function genetic mouse models
| Genes . | Blood vessel phenotype . | Lymphatic vessel phenotype . |
|---|---|---|
| Ligands and receptors | ||
| Vegf-c | Vegfc−/−: Normal developmental angiogenesis44 | Vegfc−/−: No sprouting of LECs, absence of lymphatic vessels44 Vegfc+/−: Chylous ascites, hypoplasia44 |
| Vegfr-3 | Vegfr3−/−: Early blood vessel remodeling defects, death at E9.5-1048 Vegfr3f/f;Pdgfb-CreERT2: Vessel hypersprouting114 | Vegfr3+/Chy: Chylous ascites, hypoplasia50 Vegfr3ΔLBD/ΔLBD: No sprouting of LECs due to the removal of ligand-binding (LBD) domain of Vegfr-3115 |
| Nrp2 | Nrp2−/−: Normal developmental angiogenesis54 | Nrp2−/−: Hypoplasia of capillaries E13 to birth54 Nrp2+/−;Vegfr3+/−: Decreased vessel sprouting55 |
| EphrinB2 | Efnb2f/f;Cdh5-CreERT2: Reduced vascular network complexity, sprouting and endothelial cell proliferation74 Efnb2ΔV/ΔV: Normal developmental angiogenesis72 | Efnb2f/f;Cdh5-CreERT2: Decreased vessel sprouting74 Efnb2ΔV/ΔV: Defective lymphatic vascular remodeling, hyperplasia, valve agenesis72,74 |
| Vegfr-2 | Vegfr2−/−: Lack of development of the blood islands and embryonic vasculature, death at E8.5-E9.5116 Vegfrf/f;Lyve-1Cre: Decreased blood vessel density in the yolk sac, liver and lung60 | Vegfrf/f;Lyve-1Cre: Hypoplasia, decreased vessel sprouting60 |
| Bmp9 | Bmp9−/−: No phenotype in the retinal blood vessels117 | Bmp9−/−: Postnatal vessel hyperplasia, decreased maturation of valves. Adults: enlarged lymphatics, decreased number of lymphatic valves, impaired lymph drainage109,110 |
| TGFβ2 | Tgfb2−/−: Blood vascular remodeling occurs normally108 | Tgfb2−/−: Mild edema, increased cellular proliferation, decreased complexity and sprouting, enlarged vessels108 |
| TGFβRI | TgfbrIf/f;Tie1Cre: Defective vascular network, pericardial effusion in the heart, abnormalities in the vasculature of the yolk sac at E9.5, lethal at E10.5103 TgfbrIf/f;Tie2Cre: Hypoplastic endocardial cushion in the arterio-ventricular canal; thinner, poorly trabeculated myocardium, lethal soon after E13118 TgfbrIf/f;Alk1GFPCre/+: Enlarged pericardial cavity, underdeveloped heart, lethal at E14.5102 | TgfbrIf/fProx1+/GFPCre: Deletion at E9.5-10.5. Edema at E14.5 with blood filled lymphatics. Lymphatic network and sprouting reduction106 TgfbrIf/f;Prox1-CreERT2: Deletion at E12.5 impaired cell sprouting and hyperplasia106 TgfbrIf/f;VEC-CreERT2: Deletion at E12.5, mild edema, hyperplasia, lymphatic network and sprouting reduction106 |
| TGFβRII | TgfbrIIf/f;Tie1Cre: Pericardial effusion in the heart, abnormalities in the vasculature of the yolk sac at E9.5, lethal at around E10.5103 TgfbrIIf/fl;Tie2Cre: Cardiac defects and lethality at around E12.5119 TgfbrIIf/f;Pdgfb-CreERT2: Hemorrhagic blood vessels in retina, impaired vascular development96 | TgfbrIIf/f;Prox1+/GFPCre: Deletion at E9.5-10.5. Edema at E14.5 with blood – filled lymphatics. Lymphatic network and sprouting reduction106 TgfbrIIf/f;Prox1-CreERT2: Deletion at E12.5 presence of dysmorphogenic lymphatic vessels and reduced lymphatic branching106 TgfbrIIf/f;VEC-CreERT2: Deletion at E12.5, mild edema, hyperplasia, lymphatic network and sprouting reduction106 |
| Notch1 | Notch1f/f;Cdh5-CreERT2: Regional retinal vessel hypersprouting120 | Notch1f/f;Prox1CreERT2: Overproduction of LECs, edema, blood-filled lymphatics and incorporation of BECs into the peripheral lymphatics95 |
| Ccbe1 | Ccbe1−/−: Normal physiological angiogenesis66 | Ccbe1−/−: No sprouting of LECs, absence of lymphatic vessels66 Ccbe1+/−: Early irregular formation of intersegmental veins; no lymphatic phenotype later7 |
| Angipoietins/Tie | Angpt1−/−, Tie1−/−, Tie2−/−: Defective embryonic blood vessel remodeling, lethality at E12.548121 Angpt2−/−: Normal embryonic angiogenesis, defective hyaloid vessel regression82 | Angpt2−/−: Hypoplasia of lymphatic capillaries, failure to form collecting vessels82,83 Tie1−/−: Abnormal patterning, dilated and disorganized lymphatic vessels80,81 |
| Intracellular pathways | ||
| H/N/Kras | Nras+/−;Kras+/−: Normal developmental angiogenesis122 | Nras+/−;Kras+/−: Lymphatic hypoplasia, chylous ascites122 |
| Rasa1 | Rasa1−/−: Early blood vascular remodeling defects, lethality at E9.5123 Rasa1f/f;UB-ERT2Cre: Systemic inactivation in adults-normal blood vessels124 | Rasa1f/f;UB-ERT2Cre: Systemic inactivation in adults leading to hyperplasia, increased leakage, chylothorax, chylous ascites124 |
| PI3K/Akt1 | Pi3kca−/−(p85/p55/p50): Minor defects of developmental angiogenesis125 Akt1−/−: Normal physiological angiogenesis126 | Pi3kca−/−(p85/p55/p50): Impaired valve development, organ-specific hypoplasia125 Pi3kp110Rbd/Rbd: Chylous ascites, decreased branching and network complexity125 Akt1−/−: Reduced capillary density, defective valve development140 |
| Cnb1 | Cnb1f/f;Tie2-Cre: Defective coronary vasculature127 Cnb1f/f;Pdgfb-CreERT2: Normal physiological angiogenesis128 | Cnb1f/f;Prox1-CreERT2: Defective lymphatic vessel maturation and valve development128 |
| Genes . | Blood vessel phenotype . | Lymphatic vessel phenotype . |
|---|---|---|
| Ligands and receptors | ||
| Vegf-c | Vegfc−/−: Normal developmental angiogenesis44 | Vegfc−/−: No sprouting of LECs, absence of lymphatic vessels44 Vegfc+/−: Chylous ascites, hypoplasia44 |
| Vegfr-3 | Vegfr3−/−: Early blood vessel remodeling defects, death at E9.5-1048 Vegfr3f/f;Pdgfb-CreERT2: Vessel hypersprouting114 | Vegfr3+/Chy: Chylous ascites, hypoplasia50 Vegfr3ΔLBD/ΔLBD: No sprouting of LECs due to the removal of ligand-binding (LBD) domain of Vegfr-3115 |
| Nrp2 | Nrp2−/−: Normal developmental angiogenesis54 | Nrp2−/−: Hypoplasia of capillaries E13 to birth54 Nrp2+/−;Vegfr3+/−: Decreased vessel sprouting55 |
| EphrinB2 | Efnb2f/f;Cdh5-CreERT2: Reduced vascular network complexity, sprouting and endothelial cell proliferation74 Efnb2ΔV/ΔV: Normal developmental angiogenesis72 | Efnb2f/f;Cdh5-CreERT2: Decreased vessel sprouting74 Efnb2ΔV/ΔV: Defective lymphatic vascular remodeling, hyperplasia, valve agenesis72,74 |
| Vegfr-2 | Vegfr2−/−: Lack of development of the blood islands and embryonic vasculature, death at E8.5-E9.5116 Vegfrf/f;Lyve-1Cre: Decreased blood vessel density in the yolk sac, liver and lung60 | Vegfrf/f;Lyve-1Cre: Hypoplasia, decreased vessel sprouting60 |
| Bmp9 | Bmp9−/−: No phenotype in the retinal blood vessels117 | Bmp9−/−: Postnatal vessel hyperplasia, decreased maturation of valves. Adults: enlarged lymphatics, decreased number of lymphatic valves, impaired lymph drainage109,110 |
| TGFβ2 | Tgfb2−/−: Blood vascular remodeling occurs normally108 | Tgfb2−/−: Mild edema, increased cellular proliferation, decreased complexity and sprouting, enlarged vessels108 |
| TGFβRI | TgfbrIf/f;Tie1Cre: Defective vascular network, pericardial effusion in the heart, abnormalities in the vasculature of the yolk sac at E9.5, lethal at E10.5103 TgfbrIf/f;Tie2Cre: Hypoplastic endocardial cushion in the arterio-ventricular canal; thinner, poorly trabeculated myocardium, lethal soon after E13118 TgfbrIf/f;Alk1GFPCre/+: Enlarged pericardial cavity, underdeveloped heart, lethal at E14.5102 | TgfbrIf/fProx1+/GFPCre: Deletion at E9.5-10.5. Edema at E14.5 with blood filled lymphatics. Lymphatic network and sprouting reduction106 TgfbrIf/f;Prox1-CreERT2: Deletion at E12.5 impaired cell sprouting and hyperplasia106 TgfbrIf/f;VEC-CreERT2: Deletion at E12.5, mild edema, hyperplasia, lymphatic network and sprouting reduction106 |
| TGFβRII | TgfbrIIf/f;Tie1Cre: Pericardial effusion in the heart, abnormalities in the vasculature of the yolk sac at E9.5, lethal at around E10.5103 TgfbrIIf/fl;Tie2Cre: Cardiac defects and lethality at around E12.5119 TgfbrIIf/f;Pdgfb-CreERT2: Hemorrhagic blood vessels in retina, impaired vascular development96 | TgfbrIIf/f;Prox1+/GFPCre: Deletion at E9.5-10.5. Edema at E14.5 with blood – filled lymphatics. Lymphatic network and sprouting reduction106 TgfbrIIf/f;Prox1-CreERT2: Deletion at E12.5 presence of dysmorphogenic lymphatic vessels and reduced lymphatic branching106 TgfbrIIf/f;VEC-CreERT2: Deletion at E12.5, mild edema, hyperplasia, lymphatic network and sprouting reduction106 |
| Notch1 | Notch1f/f;Cdh5-CreERT2: Regional retinal vessel hypersprouting120 | Notch1f/f;Prox1CreERT2: Overproduction of LECs, edema, blood-filled lymphatics and incorporation of BECs into the peripheral lymphatics95 |
| Ccbe1 | Ccbe1−/−: Normal physiological angiogenesis66 | Ccbe1−/−: No sprouting of LECs, absence of lymphatic vessels66 Ccbe1+/−: Early irregular formation of intersegmental veins; no lymphatic phenotype later7 |
| Angipoietins/Tie | Angpt1−/−, Tie1−/−, Tie2−/−: Defective embryonic blood vessel remodeling, lethality at E12.548121 Angpt2−/−: Normal embryonic angiogenesis, defective hyaloid vessel regression82 | Angpt2−/−: Hypoplasia of lymphatic capillaries, failure to form collecting vessels82,83 Tie1−/−: Abnormal patterning, dilated and disorganized lymphatic vessels80,81 |
| Intracellular pathways | ||
| H/N/Kras | Nras+/−;Kras+/−: Normal developmental angiogenesis122 | Nras+/−;Kras+/−: Lymphatic hypoplasia, chylous ascites122 |
| Rasa1 | Rasa1−/−: Early blood vascular remodeling defects, lethality at E9.5123 Rasa1f/f;UB-ERT2Cre: Systemic inactivation in adults-normal blood vessels124 | Rasa1f/f;UB-ERT2Cre: Systemic inactivation in adults leading to hyperplasia, increased leakage, chylothorax, chylous ascites124 |
| PI3K/Akt1 | Pi3kca−/−(p85/p55/p50): Minor defects of developmental angiogenesis125 Akt1−/−: Normal physiological angiogenesis126 | Pi3kca−/−(p85/p55/p50): Impaired valve development, organ-specific hypoplasia125 Pi3kp110Rbd/Rbd: Chylous ascites, decreased branching and network complexity125 Akt1−/−: Reduced capillary density, defective valve development140 |
| Cnb1 | Cnb1f/f;Tie2-Cre: Defective coronary vasculature127 Cnb1f/f;Pdgfb-CreERT2: Normal physiological angiogenesis128 | Cnb1f/f;Prox1-CreERT2: Defective lymphatic vessel maturation and valve development128 |
RBD, Ras-binding domain.