Background and purpose: In animal models, flow loading is a necessary and sufficient hemodynamic factor to express the cerebral aneurysm (CA) phenotype. Promotional biological factors may include variant forms of the adaptive response to flow loading. Using a rat model, this study characterizes molecular events that comprise cerebral arterial responses to flow loading and reveals their significance in relation to the CA phenotype.
Methods: 32 rats underwent bilateral common carotid artery ligation (BCL) (n=16) or sham surgery (SS)(n=16). Nineteen days later, vertebrobasilar arteries were harvested, histologically examined and analyzed for mRNA and protein expression. Flow (shear) induced changes in mRNA expression, protein expression and histology were determined by comparing BCL to SS rats. Differences between aneurysm-prone (Long Evans, LE) and resistant (Brown Norway, BN) strains were evaluated.
Results: Basilar artery medial thickness/luminal diameter ratio was significantly reduced in BCL rats, without significant differences between LE (2.02 fold) and BN (1.94 fold) rats. BCL significantly altered basilar artery expression of mRNA and proteins that modulate wall structure and function but had no effect on blood pressure. Eight genes showed similarly large flow induced expression changes in LE and BN rats (TyrRS, Mfge8, Galnt13, GABRP, Pp1r1a, Dpt_predicted, Cd34_predicted, ApoE). Twenty six shear responsive genes showed significant differences in shear induced expression between LE and BN rats. The Cthrc1, Gsta3, Tgfb3, Ldha, Myo1d, Ermn, PTHrp, Rgs16 and TRCCP genes showed the strongest shear responsive expression, and the largest difference in shear responsive expression between LE and BN rats.
Conclusions: Our study reveals specific molecular biological responses involved in flow induced expansive remodeling of cerebral arteries. A group of 9 strongly shear responsive genes showed major differences in flow induced expression between LE and BN rats and are implicated as having important roles in maladaptive remodeling associated with the CA phenotype.