Rationale:: Human studies and mouse models have provided evidence for angiotensin II (Ang II)–based mechanisms as an underlying cause of aneurysms localized to the ascending aorta. In agreement with this associative evidence, we have published recently that Ang II infusion induces aneurysmal pathology in the ascending aorta. Objective:: The aim of this study was to define the role of angiotensin II type 1a (AT _1a ) receptors and their cellular location in Ang II–induced ascending aortic aneurysms (AAs). Methods and Results:: Male LDL receptor ^−/− mice were fed a saturated fat–enriched diet for 1 week before osmotic mini-pump implantation and infused with either saline or Ang II (1000 ng/kg per minute) for 28 days. Intimal surface areas of ascending aortas were measured to quantify ascending AAs. Whole body AT _1a receptor deficiency ablated Ang II–induced ascending AAs ( P <0.001). To determine the role of AT _1a receptors on leukocytes, LDL receptor ^−/− ×AT _1a receptor ^+/+ or AT _1a receptor ^−/− mice were irradiated and repopulated with bone marrow–derived cells isolated from either AT _1a receptor ^+/+ or AT _1a receptor ^−/− mice. Deficiency of AT _1a receptors in bone marrow–derived cells had no effect on Ang II–induced ascending AAs. To determine the role of AT _1a receptors on vascular wall cells, we developed AT _1a receptor floxed mice with depletion on either smooth muscle or endothelial cells using Cre driven by either SM22 or Tek, respectively. AT _1a receptor deletion in smooth muscle cells had no effect on ascending AAs. In contrast, endothelial-specific depletion attenuated this pathology. Conclusions:: Ang II infusion promotes aneurysms in the ascending aorta via stimulation of AT _1a receptors that are expressed on endothelial cells.

Our objective was to determine whether electrical neuromodulation using spinal cord stimulation (SCS) mitigates transient ischemia-induced ventricular infarction and, if so, whether adrenergic neurons are involved in such cardioprotection. The hearts of anesthetized rabbits, subjected to 30 min of left anterior descending coronary arterial occlusion (CAO) followed by 3 h of reperfusion (control), were compared with those with preemptive SCS (starting 15 min before and continuing throughout the 30-min CAO) or reactive SCS (started at 1 or 28 min of CAO). For SCS, the dorsal C8-T2 segments of the spinal cord were stimulated electrically (50 Hz, 0.2 ms, 90% of motor threshold). For preemptive SCS, separate groups of animals were pretreated 15 min before SCS onset with 1) vehicle, 2) prazosin (α₁-adrenoceptor blockade), or 3) timolol (β-adrenoceptor blockade). Infarct size (IS), measured with tetrazolium, was expressed as a percentage of risk zone. In controls exposed to 30 min of CAO, IS was 36.4 ± 9.5% (SD). Preemptive SCS reduced IS to 21.8 ± 6.8% ( P < 0.001). Preemptive SCS-mediated infarct reduction was eliminated by prazosin (36.6 ± 8.8%) and blunted by timolol (29.4 ± 7.5%). Reactive SCS did not reduce IS. SCS increased phosphorylation of cardiac PKC. SCS did not alter blood pressure or heart rate. We conclude that preemptive SCS reduces the size of infarcts induced by transient CAO; such cardioprotection involves cardiac adrenergic neurons.

Rationale : Angiotensin II (Ang II) has diverse effects on smooth muscle cells (SMCs). The diversity of effects may relate to the regional location of this cell type. Objective : The aim of this study was to define whether Ang II exerted divergent effects on smooth muscle cells in the aorta and determine the role of blood pressure and specific oxidant mechanisms. Methods and Results : Ang II (1000 ng/kg per minute) infusion for 28 days into mice increased systolic blood pressure and promoted medial expansion of equivalent magnitude throughout the entire aorta. Both effects were ablated by angiotensin II type 1a (AT _1a ) receptor deficiency. Similar increases in systolic blood pressure by administration of norepinephrine promoted no changes in aortic medial thickness. Increased medial thickness was attributable to SMC expansion owing to hypertrophy in most aortic regions, with the exception of hyperplasia of the ascending aorta. Deficiency of the p47 ^phox component of NADPH oxidase ablated Ang II–induced medial expansion in all aortic regions. Analysis of mRNA and protein throughout the aorta revealed a much higher abundance of the inhibitor of differentiation 3 (Id3) in the ascending aorta compared to all other regions. A functional role was demonstrated by Id3 deficiency inhibiting Ang II–induced SMC hyperplasia of the ascending aorta. Conclusions : In conclusion, Ang II promotes both aortic medial hypertrophy and hyperplasia in a region-specific manner via an oxidant mechanism. The ascending aortic hyperplasia is dependent on Id3.

Sympathetic nerve activity increases in the heart during cardiac failure. Here, we hypothesized that β1 integrins play a protective role in chronic β-adrenergic receptor–stimulated cardiac myocyte apoptosis and heart failure. l-isoproterenol (iso; 400 μg/kg per hour) was infused in a group of wild-type (WT) and β1 integrin heterozygous knockout (hKO) mice. Left ventricular structural and functional remodeling was studied at 7 and 28 days of iso-infusion. Western blot analysis demonstrated reduced β1 integrin levels in the myocardium of hKO-sham. Iso-infusion increased heart weight:body weight ratios in both groups. However, the increase was significantly higher in WT-iso. M-mode echocardiography indicated increased left ventricular end-diastolic diameter, percentage of fractional shortening, and ejection fraction in the WT-iso group. The percentage of fractional shortening and ejection fraction were significantly lower in hKO-iso versus hKO-sham and WT-iso. Peak left ventricular developed pressure and lef...

Rationale:: Peroxisome proliferator-activated receptor (PPAR)γ agonists attenuate atherosclerosis and abdominal aortic aneurysms (AAAs). PPARγ, a nuclear receptor, is expressed on many cell types including smooth muscle cells (SMCs). Objective:: To determine whether a PPARγ agonist reduces angiotensin II (Ang II)–induced atherosclerosis and AAAs via interaction with SMC-specific PPARγ. Methods and Results:: Low-density lipoprotein receptor (LDLR) ^−/− mice with SMC-specific PPARγ deficiency were developed using PPARγ floxed (PPARγ ^f/f ) and SM22 Cre ⁺ mice. PPARγ ^f/f littermates were generated that did not express Cre (Cre ^0/0 ) or were hemizygous for Cre (Cre ^+/0 ). To assess the contribution of SMC-specific PPARγ in ligand-mediated attenuation of Ang II–induced atherosclerosis and AAAs, both male and female Cre ^0/0 and Cre ^+/0 mice were fed a fat-enriched diet with or without the PPARγ agonist pioglitazone (Pio) (20 mg/kg per day) for 5 weeks. After 1 week of feeding modified diets, mice were infused with Ang II (1000 ng/kg per minute) for 4 weeks. SMC-specific PPARγ deficiency or Pio administration had no effect on plasma cholesterol concentrations. Pio administration attenuated Ang II–increased systolic blood pressure equivalently in both Cre ^0/0 and Cre ^+/0 groups. SMC-specific PPARγ deficiency increased atherosclerosis in male mice. Pio administration reduced atherosclerosis in only the Cre ^0/0 mice, but not in mice with SMC-specific PPARγ deficiency. SMC-specific PPARγ deficiency or Pio administration had no effect on Ang II–induced AAA development. Pio also did not attenuate Ang II–induced monocyte chemoattractant protein-1 production in PPARγ-deficient SMCs. Conclusions:: Pio attenuates Ang II–induced atherosclerosis via the interaction with SMC-specific PPARγ, but has no effect on the development of AAAs.