Constrictive vascular remodeling limiting blood flow, as well as compensatory outward remodeling, have been observed in many cardiovascular diseases; however, the underlying mechanisms regulating the remodeling response of the vessels remain unclear.
More...Constrictive vascular remodeling limiting blood flow, as well as compensatory outward remodeling, have been observed in many cardiovascular diseases; however, the underlying mechanisms regulating the remodeling response of the vessels remain unclear. Plasminogen activators (PA) are involved in many of the processes of vascular remodeling. We have shown previously that increased tissue-type PA (tPA) contributes to outward vascular remodeling. To elucidate the mechanisms involved in the induction of outward remodeling we characterized changes in the expression profiles of 8799 genes in injured rat carotid arteries one and four days after recombinant tPA treatment compared to vehicle. Periadventitial tPA significantly increased lumen size and vessel area, encompassed by the external elastic lamina, at both one and four days after treatment. Among 41 differentially expressed known genes one day after tPA application, 5 genes were involved in gene transcription, 5 genes were related to the regulation of vascular tone (for example, thromboxane A2 receptor (D32080) or nonselective-type endothelin receptor (S65355)), and 8 genes were identified as participating in vascular innervation (for example, calpain (D14478) or neural cell adhesion molecule L1 (X59149)). Four days after injury in tPA-treated arteries, 4 genes, regulating vascular tone, were differentially expressed. Thus, tPA promotes outward arterial remodeling after injury, at least in part, by regulating expression of genes in the vessel wall related to function of the nervous system and vascular tone.
Overall design: Male Wistar-Kyoto rats (3 months old) were obtained from a colony maintained at standard colony conditions including 12 h-12 h light-dark cycle, 22 ± 2 °C temperature and free access to food and water. Their left common carotid artery was subjected to balloon catheter injury using surgical procedures approved by the Cardiology Research Center's Animal Experimentation Committee. Following balloon catheter injury, 20 nmol/kg of recombinant tissue-type plasminogen activator dissolved in pluronic gel or 500 μl of plain Pluronic gel, F-127 (BASF) was applied to the adventitial side of the left common carotid arteries. Either 1 or 4 days after the experimental balloon angioplasty or sham-operated animals or intact animals were narcotized and total RNA was isolated from left carotids or right carotids of ballooned and sham-operated as well as non-operated animals (not less than 9 rats per group, 3 vessels were pooled for 1 sample). Changes in gene expression profiles were analyzed using U34A microarray hybridization (Affymetrix, Santa Clara, CA) and Quantitative Real-Time PCR (Applied Biosystems).
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