Karima Ait Aissa1, Jérémy Lagrange1, Amel Mohamadi1, Huguette Louis1, Bénédicte Houppert1, Pascal Challande1, Denis Wahl1, Patrick Lacolley1, Véronique Regnault2. 1. From the INSERM, U1116, Vandœuvre-lès-Nancy, France (K.A.A., J.L., A.M., H.L., B.H., D.W., P.L., V.R.); Université de Lorraine, Nancy, France (K.A.A., J.L., A.M., H.L., B.H., D.W., P.L., V.R.); UPMC, University of Paris, Paris, France (P.C.); and CNRS, UMR 7190, Paris, France (P.C.). 2. From the INSERM, U1116, Vandœuvre-lès-Nancy, France (K.A.A., J.L., A.M., H.L., B.H., D.W., P.L., V.R.); Université de Lorraine, Nancy, France (K.A.A., J.L., A.M., H.L., B.H., D.W., P.L., V.R.); UPMC, University of Paris, Paris, France (P.C.); and CNRS, UMR 7190, Paris, France (P.C.). veronique.regnault@inserm.fr.
Abstract
OBJECTIVE: The hypothesis that hypertension induces a hypercoagulable state arises from the complications associated with hypertension: stroke and myocardial infarction. Here, we determine whether hypertension causes changes in the thrombin-generating capacity of the vascular wall. APPROACH AND RESULTS: We used spontaneously hypertensive rats (SHR) compared with Wistar rats. The addition of thoracic aortic rings of SHR to a Wistar or SHR plasma pool resulted in a greater increase in thrombin generation compared with equivalent rings from Wistar. This increase occurred in 12- but not 5-week-old rats and was prevented by an angiotensin II-converting enzyme inhibitor, indicating that established hypertension is required to induce increased thrombin generation within the vessel wall. Whereas no difference was observed for endothelial cells, thrombin formation was higher on aortic smooth muscle cells (SMCs) from SHR than on those from Wistar. Exposure of negatively charged phospholipids was higher on SHR than on Wistar rings, as well as on cultured SMCs. Tissue factor activity was higher in SHR SMCs. Twelve-week-old SHR exhibited accelerated FeCl3-induced thrombus formation in carotid arteries, and the resulting occlusive thrombi were disaggregated by blockade of glycoprotein Ibα-von Willebrand factor interactions. SHR SMCs were more sensitive to thrombin-induced proliferation than Wistar SMCs. This effect was totally abolished by a protease-activated receptor 1 inhibitor. CONCLUSIONS: The prothrombotic phenotype of the SHR vessel wall was due to the ability of SMCs to support greater thrombin generation and resulted in accelerated occlusive thrombus formation after arterial injury, which was sensitive to glycoprotein Ibα-von Willebrand factor inhibitors.
OBJECTIVE: The hypothesis that hypertension induces a hypercoagulable state arises from the complications associated with hypertension: stroke and myocardial infarction. Here, we determine whether hypertension causes changes in the thrombin-generating capacity of the vascular wall. APPROACH AND RESULTS: We used spontaneously hypertensiverats (SHR) compared with Wistar rats. The addition of thoracic aortic rings of SHR to a Wistar or SHR plasma pool resulted in a greater increase in thrombin generation compared with equivalent rings from Wistar. This increase occurred in 12- but not 5-week-old rats and was prevented by an angiotensin II-converting enzyme inhibitor, indicating that established hypertension is required to induce increased thrombin generation within the vessel wall. Whereas no difference was observed for endothelial cells, thrombin formation was higher on aortic smooth muscle cells (SMCs) from SHR than on those from Wistar. Exposure of negatively charged phospholipids was higher on SHR than on Wistar rings, as well as on cultured SMCs. Tissue factor activity was higher in SHR SMCs. Twelve-week-old SHR exhibited accelerated FeCl3-induced thrombus formation in carotid arteries, and the resulting occlusive thrombi were disaggregated by blockade of glycoprotein Ibα-von Willebrand factor interactions. SHR SMCs were more sensitive to thrombin-induced proliferation than Wistar SMCs. This effect was totally abolished by a protease-activated receptor 1 inhibitor. CONCLUSIONS: The prothrombotic phenotype of the SHR vessel wall was due to the ability of SMCs to support greater thrombin generation and resulted in accelerated occlusive thrombus formation after arterial injury, which was sensitive to glycoprotein Ibα-von Willebrand factor inhibitors.
Authors: Jérémy Lagrange; Mélusine Didelot; Amel Mohamadi; Lucy A Walton; Saartje Bloemen; Bas de Laat; Huguette Louis; Simon N Thornton; Brian Derby; Michael J Sherratt; Bruno Fève; Pascal Challande; Riaz Akhtar; J Kennedy Cruickshank; Patrick Lacolley; Véronique Regnault Journal: Front Physiol Date: 2017-11-22 Impact factor: 4.566