Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats.

Matrix metalloproteases (MMPs) are a family of zinc peptidases involved in extracellular matrix turnover. There is evidence that increased MMP activity is involved in remodeling of resistance vessels in chronic hypertension. Thus we hypothesized that inhibition of MMP activity with doxycycline (DOX) would attenuate vascular remodeling. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with DOX (50 mg·kg(-1)·day(-1) in the drinking water) for 6 wk. Untreated SHRSP were controls. Blood pressure was measured by telemetry during the last week. Middle cerebral artery (MCA) and mesenteric resistance artery (MRA) passive structures were assessed by pressure myography. MMP-2 expression in aortas was measured by Western blot. All results are means ± SE. DOX caused a small increase in mean arterial pressure (SHRSP, 154 ± 1; SHRSP + DOX, 159 ± 3 mmHg; P < 0.001). Active MMP-2 expression was reduced in aorta from SHRSP + DOX (0.21 ± 0.06 vs. 0.49 ± 0.13 arbitrary units; P < 0.05). In the MCA, at 80 mmHg, DOX treatment increased the lumen (273.2 ± 4.7 vs. 238.3 ± 6.3 μm; P < 0.05) and the outer diameter (321 ± 5.3 vs. 290 ± 7.6 μm; P < 0.05) and reduced the wall-to-lumen ratio (0.09 ± 0.002 vs. 0.11 ± 0.003; P < 0.05). Damage after transient cerebral ischemia (transient MCA occlusion) was reduced in SHRSP + DOX (20.7 ± 4 vs. 45.5 ± 5% of hemisphere infarcted; P < 0.05). In the MRA, at 90 mmHg DOX, reduced wall thickness (29 ± 1 vs. 22 ± 1 μm; P < 0.001) and wall-to-lumen ratio (0.08 ± 0.004 vs. 0.11 ± 0.008; P < 0.05) without changing lumen diameter. These results suggest that MMPs are involved in hypertensive vascular remodeling in both the peripheral and cerebral vasculature and that DOX reduced brain damage after cerebral ischemia.

[1]  A. Dorrance,et al.  Mineralocorticoid Receptor Activation Causes Cerebral Vessel Remodeling and Exacerbates the Damage Caused by Cerebral Ischemia , 2006, Hypertension.

[2]  D. Fitchett Results of the ONTARGET and TRANSCEND studies: an update and discussion , 2008, Vascular health and risk management.

[3]  M. Cipolla,et al.  Middle Cerebral Artery Function After Stroke: The Threshold Duration of Reperfusion for Myogenic Activity , 2002, Stroke.

[4]  R. Bryan,et al.  P 2 purinoceptor-mediated dilations in the rat middle cerebral artery after ischemia-reperfusion , 1998 .

[5]  D. Ku,et al.  Transmural pressure induces matrix-degrading activity in porcine arteries ex vivo. , 1999, American journal of physiology. Heart and circulatory physiology.

[6]  M. Mulvany,et al.  Small artery structure in hypertension. Dual processes of remodeling and growth. , 1993, Hypertension.

[7]  A. Dominiczak,et al.  Myogenic and structural properties of cerebral arteries from the stroke-prone spontaneously hypertensive rat. , 2003, American journal of physiology. Heart and circulatory physiology.

[8]  M. Mulvany,et al.  Dual Processes of Remodeling and Growth , 2005 .

[9]  A. Dorrance,et al.  11beta-hydroxysteroid dehydrogenase type II inhibition causes cerebrovascular remodeling and increases infarct size after cerebral ischemia. , 2009, Endocrinology.

[10]  R. Touyz Reactive oxygen species and angiotensin II signaling in vascular cells -- implications in cardiovascular disease. , 2004, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[11]  Guohong Li,et al.  Inflammatory mechanisms in ischemic stroke: role of inflammatory cells , 2010, Journal of leukocyte biology.

[12]  Yiqian Zhu,et al.  Matrix Metalloproteinase-9 Inhibition Attenuates Vascular Endothelial Growth Factor-Induced Intracerebral Hemorrhage , 2007, Stroke.

[13]  A. Dorrance,et al.  Diet-induced obesity causes cerebral vessel remodeling and increases the damage caused by ischemic stroke. , 2009, Microvascular research.

[14]  A. Tedgui,et al.  Role of Matrix Metalloproteinases in Early Hypertensive Vascular Remodeling , 2007, Hypertension.

[15]  J. Tanus-Santos,et al.  Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension. , 2009, Free radical biology & medicine.

[16]  J. Raffetto,et al.  Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. , 2008, Biochemical pharmacology.

[17]  D. Heistad,et al.  Blood Flow Through Cerebral Collateral Vessels in Hypertensive and Normotensive Rats , 1986, Hypertension.

[18]  Gillian Murphy,et al.  Structure and function of matrix metalloproteinases and TIMPs. , 2006, Cardiovascular research.

[19]  A. McCall,et al.  Reperfusion decreases myogenic reactivity and alters middle cerebral artery function after focal cerebral ischemia in rats. , 1997, Stroke.

[20]  J. Tanus-Santos,et al.  Metalloproteinase inhibition ameliorates hypertension and prevents vascular dysfunction and remodeling in renovascular hypertensive rats. , 2008, Atherosclerosis.

[21]  T. Yoshimoto,et al.  Vasculoprotective effect of cilostazol in aldosterone-induced hypertensive rats , 2010, Hypertension Research.

[22]  J. Mintz,et al.  Obesity Increases Blood Pressure, Cerebral Vascular Remodeling, and Severity of Stroke in the Zucker Rat , 2009, Hypertension.

[23]  G. Grimby,et al.  Adaptive structural changes of the vascular walls in hypertension and their relation to the control of the peripheral resistance. , 1958, Acta physiologica Scandinavica.

[24]  R. Brentani,et al.  A simple and sensitive method for the quantitative estimation of collagen. , 1979, Analytical biochemistry.

[25]  Ernesto L. Schiffrin,et al.  Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis , 2001, Hypertension.

[26]  A. R. English α-6-Deoxyoxytetracycline III. Total and Unbound Antibiotic Serum Concentrations After Oral Administration to Mice , 1967 .

[27]  Z. Galis,et al.  This Review Is Part of a Thematic Series on Matrix Metalloproteinases, Which Includes the following Articles: Matrix Metalloproteinase Inhibition after Myocardial Infarction: a New Approach to Prevent Heart Failure? Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis: the Good, the Ba , 2022 .

[28]  A. Dorrance,et al.  A high-potassium diet reduces infarct size and improves vascular structure in hypertensive rats. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[29]  R. M. Lee,et al.  Morphology of cerebral arteries. , 1995, Pharmacology & therapeutics.

[30]  R A Swanson,et al.  A Semiautomated Method for Measuring Brain Infarct Volume , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  D. Rizzoni,et al.  Small artery structure and hypertension: adaptive changes and target organ damage. , 2005, Journal of hypertension.

[32]  J. Switzer,et al.  Minocycline to Improve Neurologic Outcome in Stroke (MINOS): A Dose-Finding Study , 2010, Stroke.

[33]  G. Rosenberg,et al.  Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. , 1998, Stroke.

[34]  B. Lévy,et al.  Hypertension and microvascular remodelling. , 2008, Cardiovascular research.

[35]  G. Baumbach,et al.  Mechanics of large and small cerebral arteries in chronic hypertension. , 1994, The American journal of physiology.

[36]  G. Baumbach,et al.  Vascular remodeling in hypertension. , 1993, Scanning microscopy.

[37]  Jeffrey A. Jones,et al.  Differential Effects of Mechanical and Biological Stimuli on Matrix Metalloproteinase Promoter Activation in the Thoracic Aorta , 2009, Circulation.

[38]  R. Bryan,et al.  P2 purinoceptor-mediated dilations in the rat middle cerebral artery after ischemia-reperfusion. , 1999, American journal of physiology. Heart and circulatory physiology.

[39]  E. Schiffrin,et al.  Endothelial Nitric Oxide Synthase Uncoupling and Perivascular Adipose Oxidative Stress and Inflammation Contribute to Vascular Dysfunction in a Rodent Model of Metabolic Syndrome , 2009, Hypertension.

[40]  A. Dorrance,et al.  Spironolactone improves structure and increases tone in the cerebral vasculature of male spontaneously hypertensive stroke-prone rats. , 2007, Microvascular research.

[41]  R. Brentani,et al.  Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections , 1979, The Histochemical Journal.

[42]  S. Glagov,et al.  Flow regulation of 72-kD collagenase IV (MMP-2) after experimental arterial injury. , 1998, Circulation.

[43]  A. Dorrance,et al.  Dietary potassium supplementation improves vascular structure and ameliorates the damage caused by cerebral ischemia in normotensive rats , 2008, Nutrition & metabolism.

[44]  G. Rosenberg,et al.  Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. , 2007, Neurosurgical focus.

[45]  G. Baumbach,et al.  Mechanics and composition of cerebral arterioles in renal and spontaneously hypertensive rats. , 1993, Hypertension.

[46]  M. Mulvany,et al.  Vascular remodelling of resistance vessels: can we define this? , 1999, Cardiovascular research.

[47]  G. Fink,et al.  Splanchnic Circulation Is a Critical Neural Target in Angiotensin II Salt Hypertension in Rats , 2007, Hypertension.

[48]  M. Rossi,et al.  Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling. , 2010, Matrix biology : journal of the International Society for Matrix Biology.

[49]  M. Cipolla,et al.  Threshold Duration of Ischemia for Myogenic Tone in Middle Cerebral Arteries: Effect on Vascular Smooth Muscle Actin , 2001, Stroke.

[50]  D. Rizzoni 2504 Small artery structure may predict outcome in hypertension , 2003 .

[51]  P. Weinstein,et al.  Reversible middle cerebral artery occlusion without craniectomy in rats. , 1989, Stroke.

[52]  D. Short,et al.  Morphology of the intestinal arterioles in chronic human hypertension. , 1966, British heart journal.