Intraluminal delivery of thrombospondin‐2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model

Abstract

In an effort to inhibit the response to vascular injury that leads to intimal hyperplasia, this study investigated the in vivo efficacy of intraluminal delivery of thrombospondin-2 (TSP-2) small interfering RNA (siRNA). Common carotid artery (CCA) balloon angioplasty injury was performed in rats. Immediately after denudation, CCA was transfected intraluminally (15 min) with one of the following: polyethylenimine (PEI)+TSP-2 siRNA, saline, PEI only, or PEI+control siRNA. CCA was analyzed at 24 h or 21 d by using quantitative real-time PCR and immunohistochemistry. TSP-2 gene and protein expression were significantly up-regulated after endothelial denudation at 24 h and 21 d compared with contralateral untreated, nondenuded CCA. Treatment with PEI+TSP-2 siRNA significantly suppressed TSP-2 gene expression (3.1-fold) at 24 h and TSP-2 protein expression, cell proliferation, and collagen deposition up to 21 d. These changes could be attributed to changes in TGF-β and matrix metalloproteinase-9, the downstream effectors of TSP-2. TSP-2 knockdown induced anti-inflammatory M2 macrophage polarization at 21 d; however, it did not significantly affect intima/media ratios. In summary, these data demonstrate effective siRNA transfection of the injured arterial wall and provide a clinically effective and translationally applicable therapeutic strategy that involves nonviral siRNA delivery to ameliorate the response to vascular injury.-Bodewes, T. C. F., Johnson, J. M., Auster, M., Huynh, C., Muralidharan, S., Contreras, M., LoGerfo, F. W., Pradhan-Nabzdyk, L. Intraluminal delivery of thrombospondin-2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model.

Deficiency of thrombospondin‐2 alleviates intimal hyperplasia in mice by modulating vascular smooth muscle cell proliferation and migration

“…21 Bodewes et al reported the expression of Tsp2 was significantly increased in rat carotid artery after balloon injury. 9 Recently, Qi et al also stated TSP2 expression was increased in the aortic tissues and plasma of aortic dissection patients. TSP2 was found to be mainly co-localized with α-SMA and slightly with CD31 rather than CD4 or CD68, implicating Tsp2 was mostly from VSMCs, some from ECs, but not from CD4 + TCs or Møs.…”

“…Deletion of Tsp1 in mice inhibited neointima formation upon carotid artery ligation via inhibition of Tsp1/integrin β 1/YAP signaling or alleviated the loss of contractile VSMCs phenotype and collagen deposition 21 . Bodewes et al reported the expression of Tsp2 was significantly increased in rat carotid artery after balloon injury 9 . Recently, Qi et al also stated TSP2 expression was increased in the aortic tissues and plasma of aortic dissection patients.…”

Thrombospondins Differentially Regulate Proteins Involved in Arterial Remodeling

“…TSP-1, an endogenous protein which is secreted by platelets in response to arterial injury, is the TSP most associated with intimal hyperplasia and arterial remodeling (Adams, 1997). TSP-2 and TSP-5 are molecules that have recently been linked to vascular remodeling and intimal hyperplasia as well; however, little is known regarding the exact role of TSP-2 and TSP-5 in the pathogenesis of intimal hyperplasia (Bodewes et al 2017, Liang et al 2015, Wang et al 2010. The similarity in the chemical structure of TSP-2 to TSP-1 may explain why TSP-1 and TSP-2 may have similar intimal hyperplastic properties (Helkin et al 2015).…”

“…The similarity in the chemical structure of TSP-2 to TSP-1 may explain why TSP-1 and TSP-2 may have similar intimal hyperplastic properties (Helkin et al 2015). In one study, TSP-2 was shown to have a potential role in promoting intimal hyperplasia after arterial injury (Bodewes et al 2017). In contrast, TSP-5 may be protective against intimal hyperplasia and vascular remodeling.…”

“…TSP-2 has been less well studied but does share some functions with TSP-1, such as inhibiting angiogenesis, inducing endothelial cell apoptosis, VSMC proliferation and migration (Helkin et al 2015). Although the functional relationship of TSP-2 to intimal hyperplasia is less established, TSP-2 induces VSMC attachment to the extracellular matrix, and is upregulated in neointimal tissues (Bodewes et al 2017). The similarity in functions are probably due to the similarity of chemical structure between TSP-1 and TSP-2 (Helkin et al 2015).…”