Bone marrow AT1 augments neointima formation by promoting mobilization of smooth muscle progenitors via platelet-derived SDF-1{alpha}.

Abstract

OBJECTIVE:

Bone marrow (BM)-derived endothelial progenitor cells (EPCs) and vascular smooth muscle progenitor cells (VPCs) contribute to neointima formation, whereas the angiotensin II (Ang II) type 1 receptor (AT(1))-mediated action on BM-derived progenitors remains undefined.

METHODS AND RESULTS:

A wire-induced vascular injury was performed in the femoral artery of BM-chimeric mice whose BM was repopulated with AT(1)-deficient (BM-Agtr1(-/-)) or wild-type (BM-Agtr1(+/+)) cells. Neointima formation was profoundly reduced by 38% in BM-Agtr1(-/-) mice. Although the number of circulating EPCs (Sca-1(+)Flk-1(+)) and extent of reendothelialization did not differ between the 2 groups, the numbers of both circulating VPCs (c-Kit(-)Sca-1(+)Lin(-)) and tissue VPCs (Sca-1(+)CD31(-)) incorporated into neointima were markedly decreased in BM-Agtr1(-/-) mice. The accumulation of aggregated platelets and their content of stromal cell-derived factor-1alpha (SDF-1alpha) were significantly reduced in BM-Agtr1(-/-) mice, accompanied by a decrease in the serum level of SDF-1alpha. Thrombin-induced platelets aggregation was dose-dependently inhibited (45% at 0.1 IU/mL, P<0.05) in Agtr1(-/-) platelets compared with Agtr1(+/+) platelets, accompanied by the reduced expression and release of SDF-1alpha.

CONCLUSIONS:

The BM-AT(1) receptor promotes neointima formation by regulating the mobilization and homing of BM-derived VPCs in a platelet-derived SDF-1alpha-dependent manner without affecting EPC-mediated reendothelialization.

• Authors: Hirokazu Yokoi, Hiroyuki Yamada, Yoshinori Tsubakimoto, Hiroki Takata, Hiroyuki Kawahito, Sou Kishida, Taku Kato, Akihiro Matsui, Hideyo Hirai, Eishi Ashihara, Taira Maekawa, Masaru Iwai, Masatsugu Horiuchi, Kouji Ikeda, Tomosaburo Takahashi, Mitsuhiko Okigaki, Hiroaki Matsubara
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 1 Pg. 60-7 (Jan 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 19834109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Chemokine CXCL12
• Cxcl12 protein, mouse
• Receptor, Angiotensin, Type 1

Topics

• Animals
• Antibodies (pharmacology)
• Blood Platelets (metabolism)
• Bone Marrow (physiology)
• Cell Lineage (physiology)
• Chemokine CXCL12 (immunology, metabolism, pharmacology)
• Endothelial Cells (cytology, metabolism)
• Hematopoietic Stem Cell Mobilization
• Hematopoietic Stem Cells (cytology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Muscle, Smooth, Vascular (cytology, metabolism)
• Platelet Aggregation (physiology)
• Receptor, Angiotensin, Type 1 (genetics, metabolism)
• Tunica Intima (cytology, metabolism)