Trophic effect of norepinephrine on arterial intima-media and adventitia is augmented by injury and mediated by different alpha 1-adrenoceptor subtypes

In vivo studies have suggested that norepinephrine (NE) directly contribute s to normal vascular wall growth and worsening of hypertrophy, atherosclero sis, and restenosis. However, it is unknown whether these effects are secon dary to hemodynamic changes caused by systemic NE or alpha -adrenoceptor (A R) antagonists. Herein, we determined if NE directly stimulates growth of m edial smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs) that we have shown express alpha1-ARs in similar abundance. The rat aorta was isol ated before injury, 4 days after, or 12 days after balloon injury, and main tained under circumferential tension in organ culture for 48 hours with 1 m u mol/L NE. Intima-media and adventitia were separated and DNA content, pro tein synthesis, and protein content measured. In uninjured aorta, NE increa sed DNA and protein content similarly in adventitia, and increased only pro tein content in intima-media, suggesting AFB proliferation and SMC hypertro phy. In vessels isolated 4 or 12 days after injury, NE increased all 3 endp oints in both layers by up to 20-fold greater than in uninjured vessels. Th ese effects were dose-dependent and were unaffected by alpha2- or beta -AR blockade (except increased DNA content in adventitia that was also inhibite d by alpha2-AR blockade). Intima-media growth was blocked by KMD3213 (alpha 1A-AR antagonist) and adventitial growth by AH11110A (alpha 1B-AR antagoni st), whereas BMY7378 (alpha 1D-AR antagonist) had no effect. NE decreased S MC marker proteins (eg, alpha -smooth muscle actin and desmin) and augmente d the changes induced by injury. These data suggest that prolonged stimulat ion of alpha 1A- and alpha 1B-ARs induces growth of SMCs and AFBs, respecti vely, that is significantly augmented by injury.