Vascular Dysfunction Induced in Offspring by Maternal Dietary Fat Involves Altered Arterial Polyunsaturated Fatty Acid Biosynthesis

Nutrition during development affects risk of future cardiovascular disease. Relatively little is known about whether the amount and type of fat in the maternal diet affect vascular function in the offspring. To investigate this, pregnant and lactating rats were fed either 7%(w/w) or 21%(w/w) fat enriched in either18:2n-6, trans fatty acids, saturated fatty acids, or fish oil. Their offspring were fed 4%(w/w) soybean oil from weaning until day 77. Type and amount of maternal dietary fat altered acetylcholine (ACh)-mediated vaso-relaxation in offspring aortae and mesenteric arteries, contingent on sex. Amount, but not type, of maternal dietary fat altered phenylephrine (Pe)-induced vasoconstriction in these arteries. Maternal 21% fat diet decreased 20:4n-6 concentration in offspring aortae. We investigated the role of Δ6 and Δ5 desaturases, showing that their inhibition in aortae and mesenteric arteries reduced vasoconstriction, but not vaso-relaxation, and the synthesis of specific pro-constriction eicosanoids. Removal of the aortic endothelium did not alter the effect of inhibition of Δ6 and Δ5 desaturases on Pe-mediated vasoconstriction. Thus arterial smooth muscle 20:4n-6 biosynthesis de novo appears to be important for Pe-mediated vasoconstriction. Next we studied genes encoding these desaturases, finding that maternal 21% fat reduced Fads2 mRNA expression and increased Fads1 in offspring aortae, indicating dysregulation of 20:4n-6 biosynthesis. Methylation at CpG −394 bp 5′ to the Fads2 transcription start site predicted its expression. This locus was hypermethylated in offspring of dams fed 21% fat. Pe treatment of aortae for 10 minutes increased Fads2, but not Fads1, mRNA expression (76%; P<0.05). This suggests that Fads2 may be an immediate early gene in the response of aortae to Pe. Thus both amount and type of maternal dietary fat induce altered regulation of vascular tone in offspring though differential effects on vaso-relaxation, and persistent changes in vasoconstriction via epigenetic processes controlling arterial polyunsaturated fatty acid biosynthesis

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Background: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and Results: We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3). Conclusions: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication

Microdialysis of large molecules

Microdialysis has been used in many tissues, including skin, brain, adipose tissue, muscle, kidney, and gastrointestinal tract, to recover low–molecular mass endogenous mediators, metabolites, and xenobiotics from the interstitial space. Recently, molecules of larger molecular mass, such as plasma proteins, cytokines, growth factors, and neuropeptides, have also been recovered successfully using larger-pore membranes. Microdialysis recovery of large molecules offers the opportunity to identify patterns of protein expression in a variety of tissue spaces and to evaluate clinically useful biomarkers of disease. From this may develop a better understanding of the disease process and its diagnosis and more targeted approaches to therapy.<br/

Modulation of microvascular function following low-dose exposure to the organophosphorous compound malathion in human skin in vivo

This study investigates whether malathion, a widely used organophosphate insecticide, has its effects on cutaneous vasculature in healthy human volunteers through its anticholinergic activity or through the modulation of other, noncholinergic pathways. Acute, low-dose exposure to malathion (10 mg/ml for 5 h under occlusive dressing) caused a significant increase in cutaneous blood flux, monitored by using laser-Doppler flowmetry and imaging. It had little effect on tissue levels of ACh, nitric oxide, and histamine assayed in dermal dialysate collected from malathion-exposed and control-treated skin. The duration of the cutaneous vascular response to exogenous ACh (2%) delivered by iontophoresis was significantly enhanced by preexposure to malathion, both &lt;1 h after its removal and 24 h later (P &lt; 0.001). At &lt;1 h, the time to 50% decay of the response was 24 ± 4 and 50 ± 8 min in control and malathion-treated skin, respectively. Malathion also enhanced the size and duration of the axon reflex-mediated vasoresponse to ACh. The increase in blood flux to malathion and the endothelium-mediated response to exogenous ACh, both in the presence and absence of malathion, were attenuated by pretreatment of the skin with atropine and local anesthesia (P &lt; 0.01). We conclude that short-term exposure to a single low dose of malathion causes prolonged modulation of the physiological function of the cutaneous vasculature and that this is, in part, through its action on acetylcholinesterase at both neuronal and nonneuronal sites

Vascular responses in the skin: an accessible model of inflammation

The skin is the most accessible organ of the human body in which to study the inflammatory process. Until recently, changes in vascular perfusion and permeability could only be superficially visualized. A novel combination of techniques has now provided the appropriate tools with which to study this more extensively in humans

Recovery of nitric oxide from acetylcholine-mediated vasodilatation in human skin in vivo

Objectives: To investigate the relative contribution of nitric oxide (NO) to the vascular and neural mechanisms underlying the ACh-induced vasodilatation in human skin.Methods: ACh was delivered to the skin of the forearm of 28 healthy volunteers using intradermal microdialysis. Subsequent changes in tissue levels of NO and histamine were measured in the dialysate outflow and the associated changes in skin blood flux followed with the use of scanning laser Doppler imaging.Results: ACh caused a dose-dependent increase in skin blood flux measured directly above the probe, associated with a twofold increase in dialysate NO. L-NAME (5 mM) delivered simultaneously via the dialysis probe totally blocked the increase in dialysate NO but only partially attenuated (~30%) the ACh-induced increase in blood flux. At concentrations ≥6.25 mM, ACh also induced a widespread flare response, up to 40 mm in width, accompanied by the sensation of itch. The flare was not blocked by L-NAME or the H1 receptor antagonist levocetirizine, but was reduced by C-fiber blockade. Dialysate histamine levels remained unchanged at all times.Conclusions: These experiments offer further insight into the use of dialysis as an experimental technique in the skin. They provide direct evidence that the skin microvascular response to ACh is only partially mediated by NO. Further they suggest that ACh at higher concentrations can induce an axon-reflex-mediated response that is independent of NO release at the site of dermal provocation or of local histamine release

Multiscale analysis of microvascular blood flow and oxygenation

The purpose of this study is to investigate the feasibility of nonlinear methods for differentiating between haemodynamic steady states as a potential method of identifying microvascular dysfunction. As conventional nonlinear measures do not take into account the multiple time scales of the processes modulating microvascular function, here we evaluate the efficacy of multiscale analysis as a better discriminator of changes in microvascular health. We describe the basis and the implementation of the multiscale analysis of the microvascular blood flux (BF) and tissue oxygenation (OXY: oxyHb) signals recorded from the skin of 15 healthy male volunteers, age 29.2 ± 8.1y (mean ± SD), in two haemodynamic steady states at 33 °C and during warming at 43 °C to generate a local thermal hyperaemia (LTH). To investigate the influence of varying process time scales, multiscale analysis is employed on Sample entropy (MSE), to quantify signal regularity and Lempel and Ziv (MSLZ) and effort to compress (METC) complexity, to measure the randomness of the time series. Our findings show that there was a good discrimination in the multiscale indexes of both the BF (p = 0.001) and oxyHb (MSE, p = 0.002; METC and MSLZ, p &lt; 0.001) signals between the two haemodynamic steady states, having the highest classification accuracy in oxyHb signals (MSE: 86.67%, MSLZ: 90.00% and METC: 93.33%). This study shows that “multiscale-based” analysis of blood flow and tissue oxygenation signals can identify different microvascular functional states and thus has potential for the clinical assessment and diagnosis of pathophysiological conditions.</p

Complexity-based analysis of microvascular blood flow in human skin

The maintenance of an adequate microvascular perfusion sufficient to meet the metabolic demands of the tissue is dependent on neural, humoral and local vaso-mechanisms that determine vascular tone and blood flow patterns within a microvascular network. It has been argued that attenuation of these flow patterns may be a major contributor to disease risk. Thus, quantitative information on the in vivo spatio-temporal behaviour of microvascular perfusion is important if we are to understand network functionality and flexibility in cardiovascular disease. Time and frequency-domain analysis has been extensively used to describe the dynamic characteristics of Laser Doppler flowmetry (LDF) signals obtained from superficial microvascular networks such as that of the skin. However, neither approach has provided definitive and consistent information on the relative contribution of the oscillatory components of flowmotion (endothelial, neurogenic, myogenic, respiratory and cardiac) to a sustained and adequate microvascular perfusion; nor advance our understanding of how such processes are collectively modified in disease. More recently, non-linear complexity-based approaches have begun to yield evidence of a declining adaptability of microvascular flow patterns as disease severity increases. In this chapter we review the utility and application of these approaches for the quantitative, mechanistic exploration of microvascular (dys)function.</p