Sensitivity to the thromboxane A2 analog U46619 varies with inner diameter in human stem villous arteries.

INTRODUCTION: The vascular resistance of stem villous arteries is determined by the balance between different contractile and relaxant agents and in the utero-placental circulation. Thromboxane A2 (TxA2), prostaglandin F2α (PGF2α) and endothelin-1 (ET-1) are considered to be among the most important contractile factors. However, it is not known if their contractile effects are consistent along the villous tree. We hypothesized that the sensitivity to different agonists could be influenced by artery diameter and thus that their contribution to placental vascular resistance may differ. METHODS: Using an isometric wire myograph, the contractility and sensitivity (pD2) to the thromboxane A2 mimetic U46619, PGF2α and ET-1 were investigated in isolated human stem villous arteries and human uterine fundus and isthmus arteries obtained from healthy, pregnant women who had experienced uncomplicated pregnancy. RESULTS: In fetal arteries, the pD2 values for U46619 correlated positively with arterial diameter with no such dependence observed for ET-1 and PGF2α. In maternal arteries, pD2 remained constant for all the agonists tested despite highly variable vessel diameter. DISCUSSION: A selective decrease in sensitivity to TxA2 receptor stimulation was observed with decreasing vascular diameter in human stem villous arteries. The contractile factors PGF2α and ET-1 show no such relationship.

Protection against high intravascular pressure in giraffe legs.

The high blood pressure in giraffe leg arteries renders giraffes vulnerable to edema. We investigated in 11 giraffes whether large and small arteries in the legs and the tight fascia protect leg capillaries. Ultrasound imaging of foreleg arteries in anesthetized giraffes and ex vivo examination revealed abrupt thickening of the arterial wall and a reduction of its internal diameter just below the elbow. At and distal to this narrowing, the artery constricted spontaneously and in response to norepinephrine and intravascular pressure recordings revealed a dynamic, viscous pressure drop along the artery. Histology of the isolated median artery confirmed dense sympathetic innervation at the narrowing. Structure and contractility of small arteries from muscular beds in the leg and neck were compared. The arteries from the legs demonstrated an increased media thickness-to-lumen diameter ratio, increased media volume, and increased numbers of smooth muscle cells per segment length and furthermore, they contracted more strongly than arteries from the neck (500 ± 49 vs. 318 ± 43 mmHg; n = 6 legs and neck, respectively). Finally, the transient increase in interstitial fluid pressure following injection of saline was 5.5 ± 1.7 times larger (n = 8) in the leg than in the neck. We conclude that 1) tissue compliance in the legs is low; 2) large arteries of the legs function as resistance arteries; and 3) structural adaptation of small muscle arteries allows them to develop an extraordinary tension. All three findings can contribute to protection of the capillaries in giraffe legs from a high arterial pressure.

Chronic mild stress-induced depression-like symptoms in rats and abnormalities in catecholamine uptake in small arteries.

OBJECTIVE: Major depression and cardiovascular diseases have a strong comorbidity; however, the reason for this is unknown. In the chronic mild stress (CMS) model of depression, only a fraction of rats develop a major feature of depression-anhedonia-like behavior, whereas other rats are stress resilient. Previous studies suggested that CMS rats also have increased total peripheral vascular resistance. METHODS: On the basis of CMS-induced changes of sucrose intake, a reliable measure for anhedonia, rats were divided into "resilient" and "anhedonic" groups. An interaction between hedonic status and vascular function was studied after 4 and 8 weeks of CMS exposure in vitro in wire myograph on saphenous arteries and mesenteric small arteries (MSAs) from these rats. RESULTS: When comparing the different experimental rat groups, arterial sensitivities to noradrenaline (NA) were similar under control conditions, but in the presence of the neuronal reuptake inhibitor cocaine, arteries from anhedonic rats were more sensitive to NA. No change in perivascular innervation was found, but elevated expression of neuronal NA transporter was detected. Inhibition of extraneuronal uptake with corticosterone (1 µM) suggests that this transport is diminished in MSAs after CMS. The corticosterone-sensitive transporter organic cation cotransporter 2 was shown to be reduced in MSAs after CMS. No CMS-induced changes in the corticosterone-sensitive transport were found in saphenous arteries. CONCLUSIONS: Our results indicate that CMS-induced depression-like symptoms in rats are associated with changes in catecholamine uptake pathways in the vascular wall, which potentially modulates the effect of sympathetic innervation of resistance arteries.

Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries.

AIMS: We have previously characterized a cGMP-dependent Ca(2+)-activated Cl(-) current in vascular smooth muscle cells (SMCs) and have shown its dependence on bestrophin-3 expression. We hypothesize that this current is important for synchronization of SMCs in the vascular wall. In the present study, we aimed to test this hypothesis by transfecting rat mesenteric small arteries in vivo with siRNA specifically targeting bestrophin-3. METHODS AND RESULTS: The arteries were tested 3 days after transfection in vitro for isometric force development and for intracellular Ca(2+) in SMCs. Bestrophin-3 expression was significantly reduced compared with arteries transfected with mutated siRNA. mRNA levels for bestrophin-1 and -2 were also significantly reduced by bestrophin-3 down-regulation. This is suggested to be secondary to specific bestrophin-3 down-regulation since siRNAs targeting different exons of the bestrophin-3 gene had identical effects on bestrophin-1 and -2 expression. The transfection affected neither the maximal contractile response nor the sensitivity to norepinephrine and arginine-vasopressin. The amplitude of agonist-induced vasomotion was significantly reduced in arteries down-regulated for bestrophins compared with controls, and asynchronous Ca(2+) waves appeared in the SMCs. The average frequency of vasomotion was not different. 8Br-cGMP restored vasomotion in arteries where the endothelium was removed, but oscillation amplitude was still significantly less in bestrophin-down-regulated arteries. Thus, vasomotion properties were consistent with those previously characterized for rat mesenteric small arteries. Data from our mathematical model are consistent with the experimental results. CONCLUSION: This study demonstrates the importance of bestrophins for synchronization of SMCs and strongly supports our hypothesis for generation of vasomotion.