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Valve-related modes of pump failure in collecting lymphatics: numerical and experimental investigation.

ABSTRACT: Lymph is transported along collecting lymphatic vessels by intrinsic and extrinsic pumping. The walls have muscle of a type intermediate between blood-vascular smooth muscle and myocardium; a contracting segment between two valves (a lymphangion) constitutes a pump. This intrinsic mechanism is investigated ex vivo in isolated, spontaneously contracting, perfused segments subjected to controlled external pressures. The reaction to varying afterload is probed by slowly ramping up the outlet pressure until pumping fails. Often the failure occurs when the contraction raises intra-lymphangion pressure insufficiently to overcome the outlet pressure, open the outlet valve and cause ejection, but many segments fail by other means, the mechanisms of which are not clear. We here elucidate those mechanisms by resort to a numerical model. Experimental observations are paired with comparable findings from computer simulations, using a lumped-parameter model that incorporates previously measured valve properties, plus new measurements of active contractile and passive elastic properties, and the dependence of contraction frequency on transmural pressure, all taken from isobaric twitch contraction experiments in the same vessel. Surprisingly, the model predicts seven different possible modes of pump failure, each defined by a different sequence of valve events, with their occurrence depending on the parameter values and boundary conditions. Some, but not all, modes were found experimentally. Further model investigation reveals routes by which a vessel exhibiting one mode of failure might under altered circumstances exhibit another.

SUBMITTER: Bertram CD

PROVIDER: S-EPMC5671905 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Valve-related modes of pump failure in collecting lymphatics: numerical and experimental investigation.

Bertram C D CD Macaskill C C Davis M J MJ Moore J E JE

Biomechanics and modeling in mechanobiology 20170711 6

Lymph is transported along collecting lymphatic vessels by intrinsic and extrinsic pumping. The walls have muscle of a type intermediate between blood-vascular smooth muscle and myocardium; a contracting segment between two valves (a lymphangion) constitutes a pump. This intrinsic mechanism is investigated ex vivo in isolated, spontaneously contracting, perfused segments subjected to controlled external pressures. The reaction to varying afterload is probed by slowly ramping up the outlet pressu ...[more]

PMID: 28699120

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Project description:The mechanisms that control phasic and tonic contractions of lymphatic vessels are poorly understood. We hypothesized that rho kinase ROCK, previously shown to increase calcium (Ca2+) sensitivity in vascular smooth muscle, enhances lymphatic contractile activity in a similar fashion. Contractions of isolated rat mesenteric lymphatic vessels were observed at a luminal pressure of 2 cm H2O in a 37°C bath. The expression of ROCK in isolated rat mesenteric lymphatic vessels was assessed by Western blotting and confocal microscopy. The role of ROCK in contractile function was tested using two specific yet structurally distinct inhibitors: H1152 (0.1-10 μM) and Y-27632 (0.5-50 μM). In addition, lymphatics were transfected with constitutively active (ca)-ROCK protein (2 μg/ml) to assess gain of contractile function. Vessel diameter and the concentration of intracellular free Ca2+ ([Ca2+]i) were simultaneously measured in a subset of isolated lymphatics loaded with the Ca2+-sensing dye fura-2. The results show expression of both the ROCK1 and ROCK2 isoforms in lymphatic vessels. Inhibition of ROCK increased lymphatic end diastolic diameter and end systolic diameter in a concentration-dependent manner. Significant reductions in lymphatic tone and contraction amplitude were observed after treatment 1-10 μM H1152 or 25-50 μM Y-27632. H1152 (10 μM) also significantly reduced contraction frequency. Transient increases in [Ca2+]i preceded each phasic contraction, however this pattern was disrupted by either 10 μM H1152 or 50 μM Y-27632 in the majority of lymphatics studied. The significant decrease in tone caused by H1152 or Y-27632 was not associated with a significant change in the basal [Ca2+]i between transients. Transfection with ca-ROCK protein enhanced lymphatic tone, but was not associated with a significant change in basal [Ca2+]i. Our data suggest that ROCK mediates normal tonic constriction and influences phasic contractions in lymphatics. We propose that ROCK modulates Ca2+ sensitivity of contractile proteins in lymphatics.

Project description:Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure. Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.

Dataset Information

Valve-related modes of pump failure in collecting lymphatics: numerical and experimental investigation.

Publications

Valve-related modes of pump failure in collecting lymphatics: numerical and experimental investigation.

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