Females prior to menopause are much less susceptible to hypertension and other cardiovascular diseases than males, indicating that gender has a protective effect in these disorders and that female sex hormones can offset some of the alterations in arteriolar function that may occur with hypertension in males. For example, flow-induced arteriolar dilation is significantly reduced in male spontaneously hypertensive rats compared to females, because of the loss of the nitric oxide (NO)-mediated portion of the response. This impairment of the NO-mediated component of flow induced dilation results in a maintained elevation of wall shear stress in the male rats, suggesting that female sex hormones play an important role in maintaining NO-dependent vasodilator responses and in preserving the regulation of arteriolar shear stress by nitric oxide. Arteriolar dilation in response to increases in perfusate flow is also impaired in isolated gracilis muscle arterioles of ovariectomized female SHRs, compared with those of intact female SHRs and ovariectomized female SHRs receiving estrogen replacement. The impaired flow induced dilation in ovariectomized female SHRs appears to be due to the loss of the NO-dependent component of shear stress-induced vascular relaxation, providing additional evidence that estrogen preserves the NO-mediated portion of flow/shear stress-induced dilation in female hypertensive rats, resulting in a lower maintained wall shear stress in the female SHRs, compared to their male counterparts. The lower wall shear stress in the females may contribute to a lowering of systemic blood pressure and to the lower incidence of cardiovascular diseases in females. In contrast, the maintained elevation of shear stress in arterioles of the male rats could trigger other pathological alterations in the vascular wall, as discussed earlier.
Norepinephrine-induced constrictions are also enhanced in arterioles of ovariectomized female SHRs compared with those of intact female SHRs and ovariectomized female SHRs receiving estrogen supplementation. These differences in norepinephrine-induced constriction of arterioles are eliminated by inhibiting NO synthesis, suggesting that estrogen also preserves the modulating effect of NO on arteriolar responses to vasoconstrictor agonists in female rats.
Although female sex hormones may attenuate endothelial dysfunction in hypertensive animals by preserving endothelium-dependent vasodilation, less is known regarding the influence of ovarian hormones on the generation of contractile substances by the endothelium. However, it appears that female sex hormones attenuate the generation of vasoconstrictor prostanoids and superoxide anion (OV) by the endothelium of mesenteric microvessels from spontaneously hypertensive rats. Microvessels from ovariec-tomized female SHRs exhibit an increased sensitivity to norepinephrine and a reduced sensitivity to acetylcholine, compared to those from intact female SHRs. Treatment with estradiol or estradiol + progesterone restores normal reactivity to norepinephrine and acetylcholine in vessels of ovariectomized female SHRs. Inhibition of cyclooxygenase and scavenging of superoxide with superoxide dismutase (SOD) also restore normal responses to norepinephrine and acetylcholine in vessels of ovariectomized female SHRs. Norepinephrine-induced release of prostaglandin F2o (PGF2o), a vasoconstrictor metabolite of the cyclooxygenase pathway of arachidonic acid metabolism, is also greater in endothelium-intact microvessels of ovariectomized female SHRs compared to those of intact female SHRs. This response is normalized by treatment with estrogen or estrogen + progesterone. Taken together, these findings suggest that estrogen may protect female SHRs against severe hypertension, not only by preserving NO-dependent dilation, but also by decreasing the synthesis of endothelium derived contracting factors such as PGH2, PGF2o, and O^2".
Angiotensin II: Biologically active peptide formed from a precursor peptide (angiotensin I) by angiotensin-converting enzyme (ACE). Angiotensin II has numerous biological actions, including vasoconstriction, stimulation of aldosterone release, stimulation of sodium reabsorption by the kidney, and regulation of vessel structure, vessel funciton, and microvessel density.
Arachidonic acid: Major lipid precursor to various eicosanoids, which are fatty acid derivatives that act as signaling molecules to mediate many biological functions. Arachidonic acid is cleaved from membrane phospholipids and converted into a variety of biologically active lipid metabolites by various enzymes, such as cyclooxygenases, to form the immediate precursor (PGH2) for various prostaglandins (e.g., prostacyclin, prostaglandin E2, prostaglandin F2o) and thromboxane A2; lipoxygenases to form leukotrienes; and cytochrome P450 enzymes to form vasodilator compounds such as eicosatrienoic acids (EETs) and vasoconstrictor compounds such as 20-hydroxyeicosatetraenoic acid (20-HETE).
Heterotrimeric G protein: Cell membrane spanning protein that binds guanosine triphosphate (GTP) and mediates the functional coupling of membrane receptors to downstream target enzymes or ion channels involved in cellular signal transduction.
Reactive oxygen species (ROS): Reactive chemical derivatives of oxygen, such as superoxide anion, hydrogen peroxide, hypochlorous acid, and hydroxyl radical. ROS can be formed by a variety of enzymes including xanthine oxidase, nitric oxide synthase (NOS), NAD(P)H oxidase, and cyclooxygenase. Elevated levels of reactive oxygen species in blood vessels cause increased oxidative stress and can contribute to vascular dysfunction in hypertension.
Transmembrane potential (Em): Electrical potential difference that exists across the cell membrane. The magnitude of Em differs among cell types, but generally ranges between — 50 mV and — 30 mV in vascular smooth muscle cells of in vivo microvessels and resistance arteries. A reduced magnitude of the Em (depolarization) is associated with contraction of the smooth muscle due to increased Ca2+ influx into the cells via voltage activated Ca2+ (CaL) channels, while an increased magnitude of Em (hyper-polarization) is associated with reduced Ca2+ influx into the cells, leading to relaxation.
Dantas, A. P., Scivoletto, R., Fortes, Z. B., Nigro, D., and Carvalho, M. H. (1999). Influence of female sex hormones on endothelium-derived vasoconstrictor prostanoid generation in microvessels of spontaneously hypertensive rats. Hypertension 34, 914—919.
Huang, A., Sun, D., Kaley, G., and Koller, A. (1998). Superoxide release to high intra-arteriolar pressure reduces nitric oxide-mediated shear stress- and agonist-induced dilations. Circ. Res. 83, 960-965. This study demonstrated that elevated pressure in arterioles can cause increased superoxide production, which could subsequently lead to impaired dilation of arterioles in response to elevated shear stress and other NO-dependent vasodilator stimuli. These findings may be directly relevant to the impairment of vascular relaxation that occurs in hypertensive individuals not exhibiting other alterations that may impair vascular relaxation mechanisms, such as diabetes or low circulating ANG II levels.
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Lombard, J. H., Sylvester, F. A., Phillips, S. A., and Frisbee, J. C. (2003). High salt diet impairs vascular relaxation mechanisms in rat middle cerebral arteries. Am. J. Physiol. 284, H1124-H1133.
Special Topics Issue: Microcirculatory Adaptations to Hypertension. (2002). Microcirculation 9(4), 221-328. This special issue of Microcirculation features a collection of recent reviews about various aspects of microcirculatory adaptations to hypertension, including: (1) "Microvascular structure and function in salt-sensitive hypertension," by M. A. Boegehold (pp. 225—241); (2) "New expression profiles of voltage-gated ion channels in arteries exposed to high blood pressure," by R. H. Cox and N. J. Rusch (pp. 243—257); (3) "The inflammatory aspect of the microcirculation in hypertension: Oxidative stress, leuko-cytes/endothelial interaction, apoptosis," by M. Suematsu, H. Suzuki H, F. A. Delano, and G. W. Schmid-Schonbein (pp. 259—276); (4) "Signaling pathways of mechanotransduction in arteriolar endothelium and smooth muscle cells in hypertension," by A. Koller (pp. 277—294); (5) "Adaptation of resistance arteries to increases in pressure," by R. L. Prewitt, D. C. Rice, and A. D. Dobrian (pp. 295—304); (6) "Structural adaptation of microvascular networks and development of hypertension," by A. R. Pries and T. W. Secomb (pp. 305—314); and (7) "Adaptations of the renal microcirculation to hypertension," by J. D. Imig and E. W. Inscho (pp. 315-328).
Stekiel, W. J., Contney, S. J., and Rusch, N. J. (1993). Altered b-receptor control of in situ membrane potential in hypertensive rats. Hypertension 21, 1005-1009. This study demonstrated that receptor-G-protein coupling is impaired in arterioles and venules of rats with reduced renal mass hypertension. VSM transmembrane potential (Em) was measured with glass microelectrodes in first order arterioles and venules of the in situ cremaster muscle of hypertensive and normotensive rats. Arterioles of hypertensive rats failed to hyperpolarize in response either to the cAMP-dependent beta adrenergic agonist isoproterenol or to cholera toxin, a direct activator of the alpha subunit of the Gs protein coupling the receptor to downstream signaling events. In contrast, arterioles of normotensive controls hyperpolarized in response to both isoproterenol and cholera toxin. Subsequent studies by other laboratories demonstrated that G protein coupling is impaired in other forms of hypertension such as SHRs, and in animals on high salt diet. Winner (W. J. Stekiel) of the 1993 Harry Goldblatt Award in Cardiovascular Research, awarded by the publications committee of the American Heart Association Council for High Blood Pressure Research, to recognize the most significant new contribution to the understanding of the causes and/or consequences of hypertension.
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Dr. Lombard is currently Professor of Physiology at the Medical College of Wisconsin. He is a former President of the Microcirculatory Society and is a fellow of the Cardiovascular Section of the American Physiological Society, the Council for High Blood Pressure Research of the American Heart Association, and the Council on Basic Cardiovascular Sciences of the American Heart Association. His laboratory focuses on micro-circulatory control under normal conditions and during pathological conditions such as hypertension. His work is currently supported by several grants from the National Institutes of Health.
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