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cGMP-dependent protein kinase I is crucial for angiogenesis and postnatal vasculogenesis.

Aicher A, Heeschen C, Feil S, Hofmann F, Mendelsohn ME, Feil R, Dimmeler S - PLoS ONE (2009)

Bottom Line: Bone marrow progenitors from cGKI(-/-) mice showed reduced proliferation and survival rates.In addition, we used cGKIalpha leucine zipper mutant (LZM) mice as model for cGKI deficiency.Consistently, LZM mice exhibited reduced numbers of vasculogenic progenitors and impaired neovascularization following hindlimb ischemia compared to WT mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine III, JW Goethe University, Frankfurt, Germany. aicher_a@yahoo.com

ABSTRACT

Background: Endothelium-derived nitric oxide plays an important role for the bone marrow microenvironment. Since several important effects of nitric oxide are mediated by cGMP-dependent pathways, we investigated the role of the cGMP downstream effector cGMP-dependent protein kinase I (cGKI) on postnatal neovascularization.

Methodology/principal findings: In a disc neovascularization model, cGKI(-/-) mice showed an impaired neovascularization as compared to their wild-type (WT) littermates. Infusion of WT, but not cGKI(-/-) bone marrow progenitors rescued the impaired ingrowth of new vessels in cGKI-deficient mice. Bone marrow progenitors from cGKI(-/-) mice showed reduced proliferation and survival rates. In addition, we used cGKIalpha leucine zipper mutant (LZM) mice as model for cGKI deficiency. LZM mice harbor a mutation in the cGKIalpha leucine zipper that prevents interaction with downstream signaling molecules. Consistently, LZM mice exhibited reduced numbers of vasculogenic progenitors and impaired neovascularization following hindlimb ischemia compared to WT mice.

Conclusions/significance: Our findings demonstrate that the cGMP-cGKI pathway is critical for postnatal neovascularization and establish a new role for cGKI in vasculogenesis, which is mediated by bone marrow-derived progenitors.

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Neovascularization capacity in an unilateral hindlimb ischemia model using LZM and WT mice.(A) Perfusion is measured as relative Laser Doppler-derived blood flow (n≥5). (B) Number of CD31+ capillaries / mm2 in ischemic hindlimbs of LZM versus WT littermates mice (n = 12–18 sections from 4–6 mice / group).
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pone-0004879-g005: Neovascularization capacity in an unilateral hindlimb ischemia model using LZM and WT mice.(A) Perfusion is measured as relative Laser Doppler-derived blood flow (n≥5). (B) Number of CD31+ capillaries / mm2 in ischemic hindlimbs of LZM versus WT littermates mice (n = 12–18 sections from 4–6 mice / group).

Mentions: The cGKI−/− mice used for the above experiments show multiple phenotypes and a reduced life expectancy, which complicates long-term experiments with adult mice and excludes assessment of neovascularization in ischemia models [18], [19]. To validate the results obtained in juvenile cGKI−/− mice in an adult model of cGKI deficiency, we also examined the neovascularization capacity of so-called LZM mice [21]. LZM mice carry a mutation in the NH2-terminal protein interaction domain of cGKIα that results in disruption of cGKIα interactions with key downstream signaling molecules like myosin phosphatase and Rho kinase, but does not reduce the life span of the mutant mice. In line with the results from juvenile cGKI−/− mice, we observed in LZM mice a reduced neovascularization capacity, measured as relative Laser Doppler-derived blood flow, in a model of hindlimb ischemia (Fig. 5A). In addition, the vessel density assessed as number of CD31+ capillaries was lower in LZM mice (Fig. 5B). Consistently, the number of spleen-derived vasculogenic progenitor cells and vasculogenic colonies was also decreased in LZM mice (Fig. 6A+B). The reduced number and colony formation of vasculogenic progenitors might be involved in the impaired neovascularization of LZM mice. These results suggest that cGKIα in vasculogenic progenitors is also involved in the neovascularization response following ischemia.


cGMP-dependent protein kinase I is crucial for angiogenesis and postnatal vasculogenesis.

Aicher A, Heeschen C, Feil S, Hofmann F, Mendelsohn ME, Feil R, Dimmeler S - PLoS ONE (2009)

Neovascularization capacity in an unilateral hindlimb ischemia model using LZM and WT mice.(A) Perfusion is measured as relative Laser Doppler-derived blood flow (n≥5). (B) Number of CD31+ capillaries / mm2 in ischemic hindlimbs of LZM versus WT littermates mice (n = 12–18 sections from 4–6 mice / group).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654072&req=5

pone-0004879-g005: Neovascularization capacity in an unilateral hindlimb ischemia model using LZM and WT mice.(A) Perfusion is measured as relative Laser Doppler-derived blood flow (n≥5). (B) Number of CD31+ capillaries / mm2 in ischemic hindlimbs of LZM versus WT littermates mice (n = 12–18 sections from 4–6 mice / group).
Mentions: The cGKI−/− mice used for the above experiments show multiple phenotypes and a reduced life expectancy, which complicates long-term experiments with adult mice and excludes assessment of neovascularization in ischemia models [18], [19]. To validate the results obtained in juvenile cGKI−/− mice in an adult model of cGKI deficiency, we also examined the neovascularization capacity of so-called LZM mice [21]. LZM mice carry a mutation in the NH2-terminal protein interaction domain of cGKIα that results in disruption of cGKIα interactions with key downstream signaling molecules like myosin phosphatase and Rho kinase, but does not reduce the life span of the mutant mice. In line with the results from juvenile cGKI−/− mice, we observed in LZM mice a reduced neovascularization capacity, measured as relative Laser Doppler-derived blood flow, in a model of hindlimb ischemia (Fig. 5A). In addition, the vessel density assessed as number of CD31+ capillaries was lower in LZM mice (Fig. 5B). Consistently, the number of spleen-derived vasculogenic progenitor cells and vasculogenic colonies was also decreased in LZM mice (Fig. 6A+B). The reduced number and colony formation of vasculogenic progenitors might be involved in the impaired neovascularization of LZM mice. These results suggest that cGKIα in vasculogenic progenitors is also involved in the neovascularization response following ischemia.

Bottom Line: Bone marrow progenitors from cGKI(-/-) mice showed reduced proliferation and survival rates.In addition, we used cGKIalpha leucine zipper mutant (LZM) mice as model for cGKI deficiency.Consistently, LZM mice exhibited reduced numbers of vasculogenic progenitors and impaired neovascularization following hindlimb ischemia compared to WT mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine III, JW Goethe University, Frankfurt, Germany. aicher_a@yahoo.com

ABSTRACT

Background: Endothelium-derived nitric oxide plays an important role for the bone marrow microenvironment. Since several important effects of nitric oxide are mediated by cGMP-dependent pathways, we investigated the role of the cGMP downstream effector cGMP-dependent protein kinase I (cGKI) on postnatal neovascularization.

Methodology/principal findings: In a disc neovascularization model, cGKI(-/-) mice showed an impaired neovascularization as compared to their wild-type (WT) littermates. Infusion of WT, but not cGKI(-/-) bone marrow progenitors rescued the impaired ingrowth of new vessels in cGKI-deficient mice. Bone marrow progenitors from cGKI(-/-) mice showed reduced proliferation and survival rates. In addition, we used cGKIalpha leucine zipper mutant (LZM) mice as model for cGKI deficiency. LZM mice harbor a mutation in the cGKIalpha leucine zipper that prevents interaction with downstream signaling molecules. Consistently, LZM mice exhibited reduced numbers of vasculogenic progenitors and impaired neovascularization following hindlimb ischemia compared to WT mice.

Conclusions/significance: Our findings demonstrate that the cGMP-cGKI pathway is critical for postnatal neovascularization and establish a new role for cGKI in vasculogenesis, which is mediated by bone marrow-derived progenitors.

Show MeSH
Related in: MedlinePlus