Arteriosclerosis, Thrombosis, and Vascular Biology

Abstract The relationships of cell cholesterol efflux to HDL phospholipid (PL) content and composition in human serum were analyzed in two groups of subjects selected on the basis of their HDL cholesterol (HDL-C) levels: a norm-HDL group (1.10 mmol/L<HDL-C<1.50 mmol/L) and a high-HDL group (HDL-C>1.75 mmol/L). In the high-HDL group, the relative fractional efflux was significantly higher than in the norm-HDL group, and in both groups, fractional efflux was correlated with a number of lipoprotein parameters, the best correlation and the only one that remained significant after multivariate analysis being with HDL phospholipid (HDL-PL). Analysis of the HDL-PL subclasses revealed that HDL in the high-HDL sera was enriched with phosphatidylethanolamine (HDL-PE) and relatively deficient in sphingomyelin (HDL-SM) compared with norm-HDL sera. Moreover, the fractional efflux values in the high-HDL group were negatively correlated with the proportion of HDL-PE ( r =−.64, P <.0001) and positively correlated with the proportion of HDL-SM ( r =.43, P <.01). Thus, this study provides evidence that HDL-PL concentration can be used to predict the capacity of serum to accept cellular cholesterol. Among the differences described between norm-HDL and high-HDL sera, the variability in PE to SM ratio might reflect changes in serum cholesterol acceptors that modulate the first step of reverse cholesterol transport.

Numerous reports document the role of vascular adhesion molecules in the development and progression of atherosclerosis. Recent novel findings in the field of adhesion molecules require an updated summary of current research. In this review, we highlight the role of vascular adhesion molecules including selectins, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule1 (ICAM-1), PECAM-1, JAMs, and connexins in atherosclerosis. The immune system is important in atherosclerosis, and significant efforts are under way to understand the vascular adhesion molecule–dependent mechanisms of immune cell trafficking into healthy and atherosclerosis-prone arterial walls. This review focuses on the role of vascular adhesion molecules in the regulation of immune cell homing during atherosclerosis and discusses future directions that will lead to better understanding of this disease.

Objective— The immune system is thought to play a crucial role in regulating collateral circulation (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease. Here, we studied the role of lymphocytes in a murine model of hindlimb ischemia.

Methods and Results— Lymphocytes, detected with markers for NK1.1, CD3, and CD4, invaded the collateral vessel wall. Arteriogenesis was impaired in C57BL/6 mice depleted for Natural Killer (NK)-cells by anti-NK1.1 antibodies and in NK-cell–deficient transgenic mice. Arteriogenesis was, however, unaffected in Jα281-knockout mice that lack NK1.1 ⁺ Natural Killer T (NKT)-cells, indicating that NK-cells, rather than NKT-cells, are involved in arteriogenesis. Furthermore, arteriogenesis was impaired in C57BL/6 mice depleted for CD4 ⁺ T-lymphocytes by anti-CD4 antibodies, and in major histocompatibility complex (MHC)-class-II–deficient mice that more selectively lack mature peripheral CD4 ⁺ T-lymphocytes. This impairment was even more profound in anti-NK1.1-treated MHC-class-II–deficient mice that lack both NK- and CD4 ⁺ T-lymphocytes. Finally, collateral growth was severely reduced in BALB/c as compared with C57BL/6 mice, 2 strains with different bias in immune responsiveness.

Conclusions— These data show that both NK-cells and CD4 ⁺ T-cells modulate arteriogenesis. Promoting lymphocyte activation may represent a promising method to treat ischemic disease.

Objective— Blood flow is altered in metabolic and ischemic diseases with dramatic consequences. Resistance arteries structure and function remodel in response to chronic blood flow changes through a mechanism remaining mainly unknown. We hypothesized that the NO pathway and matrix metalloproteases (MMPs) activation might play a role in flow (shear stress)-induced microvascular remodeling.

Methods and Results— Mesenteric resistance arteries were ligated to alter blood flow in vivo for 4 or 14 days: arteries were submitted to high (HF), low (LF), or normal flow (NF). Rats were treated with L-NAME, the angiotensin converting enzyme inhibitor perindopril or the MMPs inhibitor doxycycline. After 14 days, outward hypertrophic remodeling occurred in HF arteries in association with eNOS overexpression. MMP9 activity increased in the early phase (day 4). HF-remodeling was prevented by L-NAME, eNOS gene knockout, and doxycycline. L-NAME prevented eNOS overexpression and MMPs activation whereas doxycycline only prevented MMPs activation. In LF arteries diameter reduction was associated with a decreased eNOS expression without change in MMPs expression and activation. LF-remodeling was reduced by perindopril.

Conclusions— In resistance arteries, high flow induced diameter enlargement and wall hypertrophy associated with the sequential activation of eNOS and MMP9.

The vascular system forms as a branching network of endothelial cells that acquire identity as arterial, venous, hemogenic, or lymphatic. Endothelial specification depends on gene targets transcribed by Ets domain–containing factors, including Ets variant gene 2 (Etv2), together with the activity of chromatin-remodeling complexes containing Brahma-related gene-1 (Brg1). Once specified and assembled into vessels, mechanisms regulating lumen diameter and axial growth ensure that the structure of the branching vascular network matches the need for perfusion of target tissues. In addition, blood vessels provide important morphogenic cues that guide or direct the development of organs forming around them. As the embryo grows and lumen diameters increase, smooth muscle cells wrap around the nascent vessel walls to provide mechanical strength and vasomotor control of the circulation. Increasing mechanical stretch and wall strain promote smooth muscle cell differentiation via coupling of actin cytoskeletal remodeling to myocardin and serum response factor–dependent transcription. Remodeling of artery walls by developmental signaling pathways reappears in postnatal blood vessels during physiological and pathological adaptation to vessel wall injury, inflammation, or chronic hypoxia. Recent reports providing insights into major steps in vascular development are reviewed here with a particular emphasis on studies that have been recently published in Arteriosclerosis, Thrombosis, and Vascular Biology.

Flow-induced changes in vessel caliber tend to restore baseline wall shear stress (WSS) and have been reported to be endothelium-dependent. To investigate the role of endothelium-derived nitric oxide (NO) in the adaptive increase in artery diameter in response to a chronic increase in blood flow, an arteriovenous fistula was constructed between the left common carotid artery (CCA) and the external jugular vein in 22 New Zealand White rabbits, and NO synthesis was inhibited in 14 animals by long-term administration of N ^G -nitro- l -arginine-methyl ester (L-NAME) in drinking water given for 4 weeks. The remaining 8 animals served as controls. Mean arterial blood pressure was not significantly altered by L-NAME treatment (91±2 in control versus 98±3 mm Hg in L-NAME–treated rabbits). Blood flow significantly increased in the left CCA in both groups but was lower in L-NAME–treated than control animals (106.1±10.7 versus 196.2±32.3 mL/min, P <.003). The diameter of the flow-loaded left CCA also increased significantly in both groups compared with the right CCA (2.15±0.12 and 2.54±0.1 mm, respectively, P <.02), but the increase was less in the L-NAME–treated than the control group (3.24±0.09 and 4.64±0.17 mm, respectively, P <.0001). The diameter of the anastomosed veins was also increased but to a much lesser degree in L-NAME–treated animals than in controls (4.14±0.29 versus 7.94±0.51 mm, P <.0001). As a result of artery enlargement, WSS was normalized in the flow-loaded left CCA of the control group (8.87±0.77 dynes/cm ² ) regardless of blood flow values. In L-NAME–treated animals, however, WSS was only partially regulated, the mean value being significantly increased (18.7±2.2 dynes/cm ² , P <.006). Moreover, a highly significant positive correlation between WSS and blood flow was obtained in L-NAME–treated animals ( r =.84, P <.0001). We also found remodeling of the artery wall, with a larger increase in the medial cross-sectional area associated with an increased number of smooth muscle cells, in the control group compared with the L-NAME–treated group (0.75±0.09 versus 0.49±0.04 mm ² and 4504±722 versus 2717±282 cells/mm ² , P <.03). We conclude that NO plays a role in the increase of vessel caliber in response to chronic increase in blood flow. As yet unidentified additional metabolic processes appear to be necessary for a complete regulatory response.