Abrupt increase in rat carotid blood flow induces rapid alteration of artery mechanical properties.

Vascular remodeling is essential to proper vessel function. Dramatic changes in mechanical environment, however, may initiate pathophysiological vascular remodeling processes that lead to vascular disease. Previous work by some of our group has demonstrated a dramatic rise in matrix metalloproteinase (MMP) expression shortly following an abrupt increase in carotid blood flow. We hypothesized that there would be a corresponding change in carotid mechanical properties. Unilateral carotid ligation surgery was performed to produce an abrupt, sustained increase in blood flow through the contralateral carotid artery of rats. The flow-augmented artery was harvested after sham surgery or 1, 2, or 6 days after flow augmentation. Vessel mechanical response in the circumferential direction was then evaluated through a series of pressure-diameter tests. Results show that the extent of circumferential stretch (normalized change in diameter) at in vivo pressure levels was significantly different (p<0.05) from normo-flow controls at 1 and 2 days following flow augmentation. Measurements at 1, 2, and 6 days were not significantly different from one another, but a trend in the data suggested that circumferential stretch was largest 1 day following surgery and subsequently decreased toward baseline values. Because previous work with this model indicated a similar temporal pattern for MMP-9 expression, an exploratory set of experiments was conducted where vessels were tested 1 day following surgery in animals treated with broad spectrum MMP inhibitors (either doxycycline or GM6001). Results showed a trend for the inhibitors to minimize changes in mechanical properties. Observations demonstrate that vessel mechanical properties change rapidly following flow augmentation and that alterations may be linked to expression of MMPs.

Roles of macrophages in flow-induced outward vascular remodeling.

Sustained hemodynamic stresses, especially sustained high blood flow, result in flow-induced outward vascular remodeling. Mechanisms that link hemodynamic stresses to vascular remodeling are not well understood. Inflammatory cells, known for their release of proteinases, including matrix metalloproteinases (MMPs), are emerging as key mediators for various tissue remodeling. Using a flow-augmented common carotid artery model in rats, we tested whether macrophages play critical roles in adaptive outward vascular remodeling in response to an increase in blood flow. Left common carotid artery ligation caused a sustained increase in blood flow with a gradual increase in luminal diameter in the right common carotid artery. Macrophages infiltrated into the vascular wall that peaked 3 days after flow augmentation. The time course of MMP-9 expression coincided with infiltration of macrophages. Macrophage depletion by liposome-encapsulated dichloromethylene diphosphonate significantly reduced flow-induced outward vascular remodeling, as indicated by the smaller luminal diameter of flow-augmented right common carotid artery in the clodronate-treated group compared with the phosphate-buffered saline-treated group (P<0.05). These data show critical roles of macrophages in flow-induced outward vascular remodeling. Inflammatory cell infiltration and their subsequent release of cytokines may be key processes for flow-induced outward vascular remodeling.

Suppression of MMP-9 by doxycycline in brain arteriovenous malformations.

BACKGROUND: The primary aim of this study is to demonstrate the feasibility of utilizing doxycycline to suppress matrix metalloproteinase-9 (MMP-9) in brain arteriovenous malformations (AVMs). METHODS: Ex-vivo treatment of AVM tissues: Intact AVM tissues were treated with doxycycline for 48 hours. Active and total MMP-9 in the medium were measured. Pilot trial: AVM patients received either doxycycline (100 mg) or placebo twice a day for one week prior to AVM resection. Active and total MMP-9 in BVM tissues were measured. RESULTS: Ex-vivo treatment of AVM tissues: Doxycycline at 10 and 100 microg/ml significantly decreased MMP-9 levels in AVM tissues ex-vivo (total: control vs 10 vs 100 microg/ml = 100 +/- 6 vs 60 +/- 16 vs 61 +/- 9%; active: 100 +/- 8 vs 48 +/- 16 vs 59 +/- 10%). Pilot trial: 10 patients received doxycycline, and 4 patients received placebo. There was a trend for both MMP-9 levels to be lower in the doxycycline group than in the placebo group (total: 2.18 +/- 1.94 vs 3.26 +/- 3.58, P = .50; active: 0.48 +/- 0.48 vs 0.95 +/- 1.01 ng/100 microg protein, P = .25). CONCLUSIONS: A clinically relevant concentration of doxycycline decreased MMP-9 in ex-vivo AVM tissues. Furthermore, there was a trend that oral doxycycline for as short as one week resulted in a decrease in MMP-9 in AVM tissues. Further studies are warranted to justify a clinical trial to test effects of doxycycline on MMP-9 expression in AVM tissues.