Abstract 1355: The Vascular Smooth Muscle Cell-Autonomous Role of Id2 in Phenotypic Modulation In Vitro And Atherogenesis In Vivo
Vascular remodeling is a fundamental process in various cardiovascular diseases including atherosclerosis. During this process, vascular smooth muscle cells (VSMCs) undergo the genetic reprogramming termed as phenotypic modulation that directs the cell migration, proliferation, secretion of proinflammatory mediators and suppression of contractile proteins. We previously reported that Inhibitor of DNA binding-2 (Id2) is the target of MAP kinase pathway that may be involved in the phenotypic modulation of VSMCs. Indeed, we found that double knockout of ApoE and Id2 (ApoE+Id2 DKO) results in 40% reduction in atheromatous area in aortae compared with ApoE single knockout (KO) mice upon atherogenic diet for 12 weeks. Because bone marrow (BM)-derived cells, in addition to VSMCs, participate in the development of atherosclerosis, we examined the role of Id2 in atherogenesis using the BM chimera. The BM from ApoE+Id2 DKO or ApoE KO mice in the background of CD45.1 was transplanted to the lethally irradiated ApoE KO mice in the background of CD45.2 at 8 weeks of age when the atherosclerotic change is still minimal. Analysis of CD45.1/.2 polymorphism in the peripheral blood leukocytes revealed that more than 90% of hematopoietic lineage cells were from the transplanted BM in the chimeric mice. The ApoE KO mice who received ApoE+Id2 DKO BM developed the equivalent extent of atheroma with those received ApoE KO BM after the 12 weeks of atherogenic diet. CD45.1/.2 staining revealed that mononuclear cells from ApoE+Id2 DKO BM populated the atheroma as efficiently as those from ApoE KO BM, suggesting that Id2 functions in atherogenesis primarily in the interstitial cells, presumably in VSMCs. To test this notion, we examined the cell-autonomous role of Id2 in the phenotypic modulation in cultured mouse VSMCs. Stimulation of wild type VSMCs with PDGF strongly suppressed SM1 isoform and induced SMemb isoform of smooth muscle myosin heavy chain, while Id2 KO VSMCs were defective in this response. Knocking down of Id2 by adenoviral expression of short hairpin RNA for Id2 also suppressed the phenotypic modulation in VSMCs. These results indicate that Id2 plays a VSMC-autonomous role in the phenotypic modulation which is essential for the full development of atherosclerosis.