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Hypertension is associated with chronic vascular inflammation. We tested the hypothesis that the sensitivity to develop hypertension and vascular remodeling depends on the immunological background. Blood pressure, vascular remodeling, endothelial function, vascular architecture (number of collateral arteries), and expression of inflammatory cytokines were determined in mice that received [N.sup.G]-nitro-L-arginine methyl ester (L-NAME) to inhibit nitric oxide synthesis. We studied C57BL/6, BALB/c, and BALB.B6-Cmvlr mice, a congenic strain where the natural killer (NK) gene complex of C57BL/6 mice is introduced in the BALB/c background. During a 4-wk treatment with L-NAME, blood pressure initially increased in both C57BL/6 and BALB/C mice, but after 4 wk, only C57BL/6 mice showed a significant increase in mean arterial blood pressure (+53 mmHg; P < 0.001) and small artery inward remodeling. Endothelial function and vascular design were significantly different between C57BL/6 mice and BALB/C mice. The inflammatory response was similar in C57BL/6 and BALB/C mice, except for the leukocyte marker CD11b. Cellular colocalization of CD11b with NK1.1 indicated the recruitment of NK cells in C57BL/6 mice. Congenic BALB.B6-Cmvlr mice showed the same endothelial response and vascular architecture as BALB/c mice. However, BALB.B6-Cmv1r mice displayed a similar sensitivity to hypertension and vascular remodeling as C57BL/6 mice. In conclusion, we have identified the NK gene complex as an important determinant in the genetically determined sensitivity to develop L-NAME-induced hypertension in mice. vascular inflammation; vascular remodeling; natural killer cells; transglutaminases; nitric oxide doi: 10.1152/ajpheart.00508.2009.

The capacity for myocardial perfusion depends on the structure of the coronary microvascular bed. Coronary microvessels may adapt their structure to various stimuli. We tested whether the local pressure profile affects tone and remodeling of porcine coronary microvessels. Subendocardial vessels (~160 [micro]m, n = 53) were cannulated and kept in organoid culture for 3 days under different transvascular pressure profiles: Osc 80: mean 80 mmHg, 60 mmHg peak-peak sine wave pulsation amplitude at 1.5 Hz; St 80: steady 80 mmHg; Osc 40: mean 40 mmHg, 30 mmHg amplitude; St 40: steady 40 mmHg. Under the Osc 80 profile, modest tone developed, reducing the diameter to 81 [+ or -] 14% (mean [+ or -] SE, n = 6) of the maximal, passive diameter. No inward remodeling was found here, as determined from the passive pressure-diameter relation after 3 days of culture. Under all other profiles, much more tone developed (e.g., Osc 40: to 26 [+ or -] 3%, n = 7). In addition, these vessels showed eutrophic (i.e., without a change in wall cross-sectional area) inward remodeling (e.g., Osc 40: passive diameter reduction by 24 [+ or -] 3%). The calcium blocker amlodipine induced maintained dilation in St 40 vessels and reversed the 22 [+ or -] 3% (n = 6) inward remodeling to 15 [+ or -] 3% (n = 8) outward remodeling toward day 3. Vessels required a functional endothelium to maintain structural integrity in culture. Our data indicate that reduction of either mean pressure or pulse pressure leads to microvascular constriction followed by inward remodeling. These effects could be reversed by amlodipine. Although microvascular pressure profiles distal to stenoses are poorly defined, these data suggest that vasodilator therapy could improve subendocardial microvascular function and structure in coronary artery disease. coronary circulation; microcirculation; vascular remodeling; amlodipine doi:10.1152/ajpheart.00711.2005

The mechanisms of flow-induced vascular remodeling are poorly understood, especially in the coronary microcirculation. We hypothesized that application of flow in small coronary arteries in organoid culture would cause a nitric oxide (NO)-mediated dilation and inhibit inward remodeling. We developed an organoid culture setup to drive a flow through cannulated arterioles at constant luminal pressure via a pressure gradient between the pipettes. Subepicardial porcine coronary arterioles with diameter at full dilation and 60 mmHg ([D.sub.0]) of 168 [+ or -] 10 (SE) [micro]m were cannulated. Vessels treated with [N.sup.[omega]]-nitro-l-arginine (L-NNA) to block NO production and untreated vessels were pressurized at 60 mmHg for 3 days with and without flow. Endothelium-dependent dilation to [10.sup.-7] M bradykinin was preserved in all groups. Tone was significantly less in vessels cultured under flow conditions in the last half of the culture period. Untreated and l-NNA-treated vessels regulated their diameter to yield shear stresses of 10.3 [+ or -] 2.1 and 14.0 [+ or -] 2.4 (SE) dyn/[cm.sup.2], respectively (not significantly different). Without l-NNA, passive pressure-diameter curves at the end of the culture period revealed inward remodeling in the control group [to 92.3 [+ or -] 1.3% of [D.sub.0] (SE)] and no remodeling in the vessels cultured under flow conditions (100.2 [+ or -] 1.3% of [D.sub.0]); with l-NNA, the group subjected to flow showed inward remodeling (92.1 [+ or -] 2.5% of [D.sub.0]). We conclude that pressurized coronary resistance arteries could be maintained in culture for several days with flow. Vessels cultured under flow conditions remained more dilated when NO synthesis was blocked. Inward remodeling occurred in vessels cultured under no-flow conditions and was inhibited by flow-dependent NO synthesis. vascular remodeling; shear stress; nitric oxide

We hypothesized that modulation of the effective charge density of the endothelial surface layer (ESL) results in altered arterial barrier properties to transport of anionic solutes. Rat mesenteric small arteries (diameter ~190 [micro]m) were isolated, cannulated, perfused, and superfused with MOPS-buffered physiological salt solutions. MOPS-solutions were of normal ionic strength (162 mM, MOPS), low ionic strength (81 mM, LO-MOPS), or high ionic strength (323 mM, HI-MOPS), to modulate ESL charge density (normal, high, or low ESL charge, respectively). Osmolarity of MOPS, LO-MOPS, and HI-MOPS was kept constant at 297 mosmol/1, using additional glucose when necessary. Perfusate solutions were supplemented with 1% BSA. Arteries were cannulated with a double-barreled theta-pipet on the inlet side and a regular pipet on the outlet side. After infusion of FITC-labeled dextran of 50 kDa (FITC-[DELTA]50) and the endothelial membrane dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, the dynamics of arterial dye tilting were determined with confocal microscopy. ESL thickness, as determined from the initial exclusion zone for FITC-[DELTA]50 on the luminal endothelial surface, was 6.3 [+ or -] 1.4 [micro]M for LO-MOPS, 2.7 [+ or -] 1.0 [micro]m for MOPS, and 1.1 [+ or -] 1.3 [micro]M for HI-MOPS. At low ionic strength, FITC-[DELTA]50 permeated into the ESL with a total ESL permeation time ([[tau].sub.ESL]) of 26 min, and at normal ionic strength with a [[tau].sub.ESL] of 20 min. No apparent exclusion of FITC-[DELTA]50 from the ESL could be observed at high ionic strength. In conclusion, we demonstrate that the modulation of solvent ionic strength influences the thickness and barrier properties of the ESL. vascular permeability; isolated artery; ionic strength; glycocalyx

Remodeling of resistance arteries in organoid culture is modulated by pressure and pressure pulsation and depends on vasomotion. Am J Physiol Heart Circ Physiol 286: H2052-H2056, 2004. First published February 12, 2004; 10.1152/ajpheart.00978.2003.--The hypothesis was tested that pressure and pressure pulsation modulate vascular remodeling. Arterioles (~200 [micro]m lumen diameter) were dissected from rat cremaster muscle and studied in organoid culture. In the first series, arterioles were kept at a stable pressure level of either 50 or 100 mmHg for 3 days. Both groups showed a progressive increase in myogenic tone during the experiment. Arterioles kept at 50 mmHg showed larger endothelium-dependent dilation, compared with vessels kept at 100 mmHg on day 3. Remodeling, as indicated by the reduction in maximally dilated diameter at 100 mmHg, was larger in arterioles kept at 50 mmHg compared with 100 mmHg: 34 [+ or -] 4.5 versus 10 [+ or -] 4.8 [micro]m (P < 0.05). In the second series, arterioles were subjected to a stable pressure of 60 mmHg or oscillating pressure of 60 [+ or -] 10 mmHg (1.5 Hz) for 4 days. Pressure pulsation induced partial dilation and was associated with less remodeling: 34 [+ or -] 4.0 versus 19 [+ or -] 4.5 [micro]m (P < 0.01) for stable pressure versus oscillating pressure. Vasomotion was frequently observed in all groups, and inward remodeling was larger in vessels with vasomotion: 30 [+ or -] 2.5 [micro]m compared with vessels that did not exhibit vasomotion: 8.0 [+ or -] 5.0 [micro]m (P < 0.01). In conclusion, these results indicate that remodeling is not enhanced by high pressure. Pressure pulsation causes partial dilation and reduces inward remodeling. The appearance of vasomotion is associated with enhanced inward remodeling. myogenic regulation; vascular adaptation; hypertension

Endothelial cells are covered by a surface layer of membrane-associated proteoglycans, glycosaminoglycans, glycoproteins, glycolipids, and associated plasma proteins. This layer may limit transendothelial solute transport. We determined dimension and transport properties of this endothelial surface layer (ESL) in isolated arteries. Rat mesenteric small arteries (diameter ~150 [micro]m) were isolated and cannulated with a double-barreled [theta]-pipette on the inlet side and a regular pipette on the outlet side. Dynamics and localization of intra-arterial fluorescence by FITC-labeled dextrans (FITC-[DELTA]s) and the endothelial membrane dye DiI were determined with confocal microscopy. Large FITC-[DELTA] (148 kDa) filled a core volume inside the arteries within 1 min but was excluded from a 2.6 [+ or -] 0.5-[micro]m-wide region on the luminal side of the endothelium during 30 min of dye perfusion. Medium FITC-[DELTA] (50.7 kDa) slowly penetrated this ESL within 30 min but did not permeate into the arterial wall. Small FITC-[DELTA] (4.4 kDa) quickly passed the ESL and accumulated in the arterial wall. Prolonged luminal fluorochrome illumination with a bright mercury lamp destroyed the ~3-[micro]m exclusion zone for FITC-[DELTA]148 within a few minutes. This study demonstrates the presence of a thick ESL that contributes to the permeability barrier to solutes. The layer is sensitive to phototoxic stress, and its damage could form an early event in atherosclerosis. vascular permeability; isolated artery; endothelial surface layer; confocal microscopy; glycocalyx

VanBavel, Ed, Pier Siersma, and Jos A.E. Spaan. Elasticity of passive blood vessels: a new concept. Am J Physiol Heart Circ Physiol 285: H1986-H2000, 2003. First published July 3, 2003; 10.1152/ajpheart.00248.2003.--The mechanical properties of passive blood vessels are generally thought to depend on the parallel arrangement of elastin and collagen with linear elasticity and collagen recruitment depending on vessel strain [hook-on (HO) model]. We evaluated an alternative model [serial element (SE) model] consisting of the series arrangement of an infinite number of elements, each containing elastin with a constant elastic modulus and collagen that switches stepwise from slack (zero stress) to fully rigid (infinite stiffness) on ongoing element strain. Both models were implemented with Weibull distributions for collagen recruitment strain (HO model) and collagen tightening strain (SE model). The models were tested in experiments on rat mesenteric small arteries. Strain-tension relations were obtained before and after two rounds of digestion by collagenase. Both models fitted the data prior to digestion. However, for the HO model, this required unrealistically low estimates for collagen recruitment or elastic modulus and unrealistically high estimates for distension of collagen fibers. Furthermore, the data after digestion were far better predicted by the SE model compared with the HO model. Finally, the SE model required one parameter less (collagen elastic modulus). Therefore, the SE model provides a valuable starting point for the understanding of vascular mechanics and remodeling of vessels. biomechanics; vascular remodeling; collagen; elastin

Myogenic response, flow-dependent dilation, and direct metabolic control are important mechanisms controlling coronary flow. A model was developed to study how these control mechanisms interact at different locations in the arteriolar tree and to evaluate their contribution to autoregulatory and metabolic flow control. The model consists of 10 resistance compartments in series, each representing parallel vessel units, with their diameters determined by tone depending on either flow and pressure [flow-dependent tone reduction factor (TR[F.sub.flow]) x [Tone.sub.myo]] or directly on metabolic factors ([Tone.sub.meta]). The pressure-[Tone.sub.myo] and flow-TR[F.sub.flow] relations depend on the vessel size obtained from interpolation of data on isolated vessels. Flow-dependent dilation diminishes autoregulatory properties compared with pressure-flow lines obtained from vessels solely influenced by [Tone.sub.myo]. By applying [Tone.sub.meta] to the four distal compartments, the autoregulatory properties are restored and tone is equally distributed over the compartments. Also, metabolic control and blockage of nitric oxide are simulated. We conclude that a balance is required between the flow-dependent properties upstream and the constrictive metabolic properties downstream. Myogenic response contributes significantly to flow regulation. myogenic response; flow-dependent dilation; metabolic control; autoregulation; mathematical model