Linoleic acid reduces vascular reactivity and improves the vascular dysfunction of the small mesentery in hypertension

We aimed to investigate the effect of linoleic acid (LA) treatment on the blood pressure and function of mesenteric resistance arteries (MRA) in spontaneous hypertensive rats (SHR). Male SHR were treated daily with LA (15 mg/kg) or vehicle (control) for 15 days. Compared with controls, LA treatment decreased blood pressure and showed the following in MRA: (1) increased lumen and external diameter, (2) decreased wall:lumen ratio and wall thickness, (3) decreased stiffness and (4) less collagen deposition. LA treatment reduced the contractile response to phenylephrine, although there were no changes observed in MRA in regard to the acetylcholine or sodium nitroprusside responses. Incubation with L-NAME left-shifted the reactivity to phenylephrine only in the MRA treated group, suggesting that LA treatment can improve NO bioavailability. This result was accompanied by an increase “in situ” NO production. Incubation with tiron decreased vascular reactivity to phenylephrine in MRA in LA rats, which was accompanied by decreased superoxide anion production. Moreover, incubation with indomethacin (non-selective COX inhibitor, 10 μM), NS 398 (COX-2 specific inhibitor, 1 μM), furegrelate (TXA₂ synthase inhibitor, 1 μM), SQ 29.548 (TP receptor antagonist, 1 μM) and SC 19220 (EP1 receptor antagonist, 10 μM) reduced the vasoconstrictor responses to phenylephrine in MRA in the treated group. These results were accompanied by a reduction in COX-2 protein expression. In conclusion, these findings show that LA treatment decreases blood pressure. In addition, the improvement of endothelial dysfunction and structural changes in this hypertension model may be responsible for the reduction in blood pressure.     

Role of vascular endothelial-cadherin in vascular morphogenesis

Vascular endothelial (VE)-cadherin is an adhesive transmembrane protein specifically expressed at interendothelial junctions. Its extracellular domain exhibits Ca2+-dependent homophilic reactivity, promoting cell-cell recognition. Mice deficient in VE-cadherin die at mid-gestation resulting from severe vascular defects. At the early phases of vascular development (E8.5) of VE-cadherin-deficient embryos, in situ differentiation of endothelial cells was delayed although their differentiation program appeared normal. Vascularization was defective in the anterior part of the embryo, while dorsal aortae and vitelline and umbilical arteries formed normally in the caudal part. At E9.25, organization of endothelial cells into large vessels was incomplete and angiogenesis was impaired in mutant embryos. Defects were more severe in extraembryonic vasculature. Blood islands of the yolk sac and clusters of angioblasts in allantois failed to establish a capillary plexus and remained isolated. This was not due to defective cell-cell recognition as endothelial cells formed intercellular junctions, as shown by electron microscopy. These data indicate that VE-cadherin is dispensable for endothelial homophilic adhesion but is required for vascular morphogenesis.     

Tempol improves vascular function in the mesenteric vascular bed of senescent rats

Ageing is associated with structural and functional alterations of the vasculature. The nature of age-related vascular disorders is not completely understood. Oxidative stress is hypothesized to play a crucial role in the pathophysiology of vascular complications. We investigated the effects of chronic treatment with the superoxide dismutase mimetic tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl) on vascular function in the mesenteric vasculature of aged rats. Young (3 weeks) and old (40 weeks) Sprague-Dawley rats were treated with tempol (1 mM in drinking water) or vehicle for 3 weeks. Arterial blood pressure was slightly, but significantly, higher in old than in young rats. Tempol had no effect on arterial blood pressure. The vasoconstrictor responses to norepinephrine (NE) and serotonin (5-HT) were exaggerated in the mesenteric vascular bed (MVB) removed from old rats. Vasodilator responses to acetylcholine (ACh), papaverine (PPV), and isoprenaline (ISO) were reduced in the MVB of old rats in comparison with young rats. Chronic treatment of old rats with tempol normalized their responses to NE and 5-HT. The dilator responses to ACh, PPV, and ISO were similar between old rats receiving tempol and young rats. The present findings suggest that oxidative stress contributes to vascular dysfunction in the mesentery of old rats. The vasculoprotective effects of tempol remain to be elucidated.     

Aldosterone and the vascular system

Aldosterone can act in different tissues exerting physiological and pathological effects. At the vascular level, aldosterone affects endothelial function since administration of aldosterone impaired endothelium-dependent relaxations. In addition, the administration of mineralocorticoid receptor antagonists ameliorate relaxation to acetylcholine in models of both hypertension and atherosclerosis and in patients with heart failure. A reduction in nitric oxide levels seems to be the main mechanism underlying this effect due to a reduction in its production as well as an increase in its degradation by reactive oxygen species. Aldosterone is a pro-inflammatory factor that can participate in the vascular inflammatory process associated with different pathologies including hypertension through activation of the NFkappaB system, which mediates the vascular production of different cytokines. This mineralocorticoid also participates in the vascular remodeling observed in hypertensive rats since the administration of eplerenone improved the media-to-lumen ratio in these animals. This effect seems to be due to an increase in extracellular matrix. In summary, aldosterone through mineralocorticoid receptors can participate in the vascular damage associated with different pathologies including hypertension through its prooxidant, pro-inflammatory and profibrotic effects that triggered endothelial dysfunction, an inflammatory process and vascular remodeling.     

Distributions of vascular pressure and resistance in the lung

The low-viscosity bolus method was used to determine the longitudinal distributions of vascular resistance and intravascular pressure with respect to cumulative vascular volume from the lobar artery to the lobar vein in isolated dog lung lobes near functional residual capacity under zone 3 conditions. We found that the resistance distribution had two modes, a larger one upstream and a smaller one downstream from a local minimum. Over the range of vascular pressures studied the total vascular resistance decreased and the vascular volume increased with increasing vascular pressure. However, the shape of the normalized resistance distribution was independent of vascular pressure. Comparisons of the resistance distributions with the distributions of arterial, capillary, and venous volumes suggest that the modes represent regions of relatively high resistance proximal and distal to the capillary bed. These results are consistent with the concept that within the lobar vascular bed the highest resistance per unit blood volume is in the smallest arteries and veins, as suggested by morphometric data from other sources.     

Expression and function of osteopontin in vascular adventitial fibroblasts and pathological vascular remodeling

Osteopontin is known to play important roles in various diseases including vascular disorders. However, little is known about its expression and function in vascular adventitial fibroblasts. Adventitial fibroblasts have been shown to play a key role in pathological vascular remodeling associating with various vascular disorders. In this study, we measured activation of Osteopontin and its biological functions in cultured adventitial fibroblasts and injured rat carotid injury arteries induced by balloon angioplasty. Our results showed that angiotensin II and aldosterone increased Osteopontin expression in adventitial fibroblasts in a time- and concentration-dependent manner. MAPKs and AP-1 pathways were involved in Osteopontin upregulation. In addition, Adventitial fibroblast migration stimulated by Angiotensin II and aldosterone required OPN expression. Perivascular delivery of antisense oligonucleotide for Osteopontin suppressed neointimal formation post-injury. We concluded that upregulation of Osteopontin expression in adventitial fibroblasts might be important in the pathogenesis of vascular remodeling after arterial injury.     

Effects of estrogens and selective estrogen receptor modulators on vascular reactivity in the perfused mesenteric vascular bed

Estrogens and selective estrogen receptor modulators (SERMs), such as raloxifene (RAL) and tamoxifen (TAM), acutely relax arteries, but the long-term effects of estrogens and SERMs on vascular reactivity in the mesenteric vasculature have not been well defined. In this study, we used an isolated, perfused mesenteric vascular bed technique to investigate the effect of chronic treatment of estrogens and SERMs on vascular reactivity of the mesenteric bed. Ovariectomized female Sprague-Dawley rats were treated by gavage with vehicle (control, 2-hydroxypropyl-beta-cyclodextrin), ethinyl estradiol, estradiol benzoate, equilin (EQ), TAM, or RAL for 3 wk. EQ and TAM increased vasoconstriction in response to all three vasoconstrictors tested (KCl, norepinephrine, and 5-HT). Ethinyl estradiol increased vasoconstriction in response to KCl and 5-HT, whereas responses to estradiol benzoate and RAL were less consistent. Only EQ (134 +/- 4 mmHg) and TAM (104 +/- 4 mmHg) changed mean arterial blood pressure compared with control (117 +/- 4 mmHg). These data demonstrate that 3-wk gavage treatment with estrogens and SERMs affects vascular reactivity in the mesenteric vascular bed. However, the three formulations of estrogen did not produce equivalent effects, and the effects of the SERMs were different from those of the estrogens.     

The extracellular matrix and the control of proliferation of vascular endothelial and vascular smooth muscle cells

In this short review we describe the observations which have led us to conclude that one of the most important components involved in modulating cell proliferation in vitro, and probably in vivo as well, may be the extrac-cellular matrix upon which cells rest.     

Increased lipogenesis and stearate accelerate vascular calcification in calcifying vascular cells

Vascular calcification is recognized as an independent predictor of cardiovascular mortality, particularly in subjects with chronic kidney disease. However, the pathways by which dysregulation of lipid and mineral metabolism simultaneously occur in this particular population remain unclear. We have shown that activation of the farnesoid X receptor (FXR) blocks mineralization of bovine calcifying vascular cells (CVCs) and in ApoE knock-out mice with 5/6 nephrectomy. In contrast to FXR, this study showed that liver X receptor (LXR) activation by LXR agonists and adenovirus-mediated LXR overexpression by VP16-LXRα and VP16-LXRβ accelerated mineralization of CVCs. Conversely, LXR inhibition by dominant negative (DN) forms of LXRα and LXRβ reduced calcium content in CVCs. The regulation of mineralization by FXR and LXR agonists was highly correlated with changes in lipid accumulation, fatty acid synthesis, and the expression of sterol regulatory element binding protein-1 (SREBP-1). The rate of lipogenesis in CVCs through the SREBP-1c dependent pathway was reduced by FXR activation, but increased by LXR activation. SREBP-1c overexpression augmented mineralization in CVCs, whereas SREBP-1c DN inhibited alkaline phosphatase activity and mineralization induced by LXR agonists. LXR and SREBP-1c activations increased, whereas FXR activation decreased, saturated and monounsaturated fatty acids derived from lipogenesis. In addition, we found that stearate markedly promoted mineralization of CVCs as compared with other fatty acids. Furthermore, inhibition of either acetyl-CoA carboxylase or acyl-CoA synthetase reduced mineralization of CVCs, whereas inhibition of stearoyl-CoA desaturase induced mineralization. Therefore, a stearate metabolite derived from lipogenesis might be a risk factor for the development of vascular calcification.     

Orestovia and the origin of vascular plants

The enigmatic Orestovia from the Lower Devonian of Siberia has a vascular cylinder of spiral and annular tracheids, external and internal cuticles in the cortex, and stomata. Abundant spores are occasionally preserved between the cortex cuticles. The 'reticulate structures' are thyriothecia of a hemisphaeriacean fungus. Spores of several types are found sticking to the cuticle. Orestovia can be conceived as a transitional form between the alga-like Protosalvinia and the sporangiate vascular plants. The origin of land plants is discussed.     

Development of the vascular bed in the rabbit ear: scanning electron microscopy of vascular corrosion casts

The development of the vascular bed in the rabbit ear was investigated using vascular corrosion casts from animals of various ages. Examination of the casts revealed that the arrangement of the major auricular arteries and veins was determined before birth and was maintained during postnatal growth of the ear. Furthermore, the number of arteries branching off the central ear artery and the lateral arteries did not increase with increasing ear length. Scanning electron microscopic examination of lateral segments of adult ear casts revealed many anastomoses between marginal arteries and veins. These arteriovenous anastomoses (AVAs) occurred singly, in pairs, or in clusters of three to six. Their size and shape were variable, even in the same cast. The central segment of many AVA casts showed surface impressions of endothelial cell nuclei which were different from the impressions on adjacent arteries and veins. Arteriovenous anastomoses were also detected in ear casts from animals as young as 8 days. The density of AVAs in lateral ear segments ranged from 95-165 cm-2 in 8- to 11-day-old rabbits to 80-115 cm-2 in adults. However, estimates of the total number of AVAs in the lateral ear margin indicated that AVAs continued to be formed at a steady rate during growth of the ear. During the early neonatal period the cutaneous capillary plexuses developed prominent tufts projecting toward the skin surface, which were apparently associated with developing hair follicles. These capillary tufts were not seen in casts from fetal or adult rabbits.     

Cardiac and vascular phenotypes in the apolipoprotein E-deficient mouse

Cardiovascular death is frequently associated with atherosclerosis, a chronic multifactorial disease and a leading cause of death worldwide. Genetically engineered mouse models have proven useful for the study of the mechanisms underlying cardiovascular diseases. The apolipoprotein E-deficient mouse has been the most widely used animal model of atherosclerosis because it rapidly develops severe hypercholesterolemia and spontaneous atherosclerotic lesions similar to those observed in humans. In this review, we provide an overview of the cardiac and vascular phenotypes and discuss the interplay among nitric oxide, reactive oxygen species, aging and diet in the impairment of cardiovascular function in this mouse model.     

Lipoprotein receptors in the vascular wall

PURPOSE OF REVIEW: We will discuss the diverse roles of lipoprotein receptors that contribute to the maintenance and integrity of the vascular wall. RECENT FINDINGS: Lipoprotein receptors function not only as transporters for cholesterol and other lipids. They also act as sensors and signal transducers through which the endothelium, macrophages and smooth muscle cells communicate with their environment. SUMMARY: Traditionally, lipoprotein receptors were thought of merely as transporters of cholesterol and triglycerides to specific target cells, either for the purpose of delivery and redistribution of nutrients, or for the destruction or clearance of modified (oxidized) lipids by macrophages. Only recently have we begun to appreciate that the same receptors engage in a much more sophisticated and multi-faceted interaction with their environment. Inasmuch, they not only act as mere transporters, but as surprisingly versatile and adaptive signal transducers and modulators throughout the vessel wall. These recent findings now begin to reshape our thinking of how such structurally different and evolutionarily unrelated lipoprotein receptors orchestrate the response of the vessel wall to mechanical or metabolic damage.