Vascular smooth muscle cells are responsible for a prothrombotic phenotype of spontaneously hypertensive rat arteries.
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.


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.
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.).
Karima
K
Ait Aissa
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.).
Jérémy
J
Lagrange
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.).
Amel
A
Mohamadi
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.).
Huguette
H
Louis
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.).
Bénédicte
B
Houppert
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.).
Pascal
P
Challande
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.).
Denis
D
Wahl
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.).
Patrick
P
Lacolley
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.
Véronique
V
Regnault
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000378:metabolism / Q000503:physiopathology; D001777:Blood Coagulation / Q000187:drug effects; D001794:Blood Pressure; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006973:Hypertension / Q000097:blood / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors; D066253:Vascular Remodeling; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D044463:Receptor, PAR-1; D014841:von Willebrand Factor; D013925:Thromboplastin; D013917:Thrombin
arteries; rats, inbred SHR; smooth muscle cells; thrombosis