Abstract-In vivo studies have suggested that norepinephrine (NE) directly contributes to normal vascular wall growth and worsening of hypertrophy, atherosclerosis, and restenosis. However, it is unknown whether these effects are secondary to hemodynamic changes caused by systemic NE or ␣-adrenoceptor (AR) antagonists. Herein, we determined if NE directly stimulates growth of medial smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs) that we have shown express ␣1-ARs in similar abundance. The rat aorta was isolated before injury, 4 days after, or 12 days after balloon injury, and maintained under circumferential tension in organ culture for 48 hours with 1 mol/L NE. Intima-media and adventitia were separated and DNA content, protein synthesis, and protein content measured. In uninjured aorta, NE increased DNA and protein content similarly in adventitia, and increased only protein content in intima-media, suggesting AFB proliferation and SMC hypertrophy. In vessels isolated 4 or 12 days after injury, NE increased all 3 endpoints in both layers by up to 20-fold greater than in uninjured vessels. These effects were dose-dependent and were unaffected by ␣2-or ␤-AR blockade (except increased DNA content in adventitia that was also inhibited by ␣2-AR blockade). Intima-media growth was blocked by KMD3213 (␣1A-AR antagonist) and adventitial growth by AH11110A (␣1B-AR antagonist), whereas BMY7378 (␣1D-AR antagonist) had no effect. NE decreased SMC marker proteins (eg, ␣-smooth muscle actin and desmin) and augmented the changes induced by injury. These data suggest that prolonged stimulation of ␣1A-and ␣1B-ARs induces growth of SMCs and AFBs, respectively, that is significantly augmented by injury. Key Words: artery Ⅲ smooth muscle cell Ⅲ adventitial fibroblast Ⅲ growth Ⅲ organ culture E ndothelial injury, eg, by balloon angioplasty, causes smooth muscle cells (SMCs) to begin proliferating within two days and to migrate to the intima where they proliferate and form lumen-narrowing lesions. 1 Recent evidence has shown that adventitial fibroblasts (AFBs) can also contribute (by as much as 50%) to neointimal lesion growth. 2,3 Wilcox et al 2 found that AFB proliferation began within hours after balloon injury and exceeded medial SMC proliferation measured over 4 weeks. Moreover, AFBs modulated to myofibroblasts, ie, ␣-smooth muscle actin (␣SM-actin) expressing cells, by one week after injury, followed by deposition of a collagen-rich adventitial thickening. Similar findings have been reported by others. 3 Whether catecholamines directly influence vascular wall growth is unknown because of difficulty in distinguishing a direct action from trophic effects of altered arterial pressure and blood flow velocity that accompany changes in sympathetic activity or plasma catecholamines. Therefore, support for this hypothesis remains indirect: (1) most large arteries are innervated with adrenergic nerves 4 ; (2) medial SMCs of large arteries express multiple ␣-adrenoceptor (AR) subtypes, several of which do not mediate constri...

Key Points Acute GVHD occurred in 5 of 9 patients after major histocompatibility–matched, T-cell–depleted peripheral blood stem cell transplantation plus IL-15/4-1BBL aNK-DLI. GVHD was more common in matched unrelated donor transplants and associated with higher CD3 chimerism, suggesting that aNK-DLI may augment T-cell alloreactivity.

Rationale Collaterals lessen tissue injury in occlusive disease. However, aging causes progressive decline in their number and smaller diameters in those that remain (collateral rarefaction), beginning at 16 months-age in mice (ie, middle age), and worse ischemic injury—effects that are accelerated in even 3 months-old eNOS−/− mice. These findings have found indirect support in recent human studies. Objective We sought to determine if other cardiovascular risk factors (CVRFs) associated with endothelial dysfunction cause collateral rarefaction, investigate possible mechanisms, and test strategies for prevention. Methods and Results Mice with nine different models of CVRFs of 4–12 months-age were assessed for number and diameter of native collaterals in skeletal muscle and brain, and for collateral-dependent perfusion and ischemic injury after arterial occlusion. Hypertension caused collateral rarefaction whose severity increased with duration and level of hypertension, accompanied by greater hindlimb ischemia and cerebral infarct volume. Chronic treatment of wildtype mice with L-NG-nitro-arginine methylester caused similar rarefaction and worse ischemic injury that were not prevented by lowering arterial pressure with hydralazine. Metabolic syndrome, hypercholesterolemia, diabetes mellitus, and obesity also caused collateral rarefaction. Neither chronic statin treatment nor exercise training lessened hypertension-induced rarefaction. Conclusion Chronic CVRF presence caused collateral rarefaction and worse ischemic injury, even at relatively young ages. Rarefaction was associated with increased proliferation rate of collateral endothelial cells, effects that may promote accelerated endothelial cell senescence.