S V Mochalov1,2,3, N V Tarasova1,2,4, T V Kudryashova5, D K Gaynullina1,2,6, V U Kalenchuk7, A S Borovik8, A V Vorotnikov5,9, O S Tarasova2,8, R Schubert1. 1. Medical Faculty Mannheim, Centre for Biomedicine and Medical Technology Mannheim (CBTM) and European Center of Angioscience (ECAS), Research Division Cardiovascular Physiology, Heidelberg University, Mannheim, Germany. 2. Faculty of Biology, M.V. Lomonosov, Moscow State University, Moscow, Russia. 3. ChemRar Research and Development Institute, Khimki, Moscow Region, Russia. 4. Molecular Medicine Institute, I.M. Sechenov First Moscow State Medical University, Moscow, Russia. 5. Institute of Experimental Cardiology, Cardiology Research Center, Moscow, Russia. 6. Department of Physiology, Russian National Research Medical University, Moscow, Russia. 7. Faculty of Basic Medicine, M.V. Lomonosov Moscow State University, Moscow, Russia. 8. State Research Center of the Russian Federation - Institute for Biomedical Problems, Russian Academy of Sciences, Moscow, Russia. 9. Medical Center, M.V. Lomonosov Moscow State University, Moscow, Russia.
Abstract
AIM: During early post-natal development, arterial contraction depends less on Ca2+ -signalling pathways but more on changes in Ca2+ -sensitivity compared to adult animals. Whether this difference is related to Rho-kinase, one of the major players affecting Ca2+ -sensitivity, is unknown for intact vessels. Thus, we tested the hypothesis that Rho-kinase critically contributes to the higher Ca2+ -sensitivity of contraction in intact arteries of 1-week-old rats. METHODS: We studied 1-week-old, 4- to 5-week-old and 10- to 12-week-old rats performing isometric myography, Ca2+ -fluorimetry and Western blotting using intact saphenous arteries and arterial pressure measurements under urethane anaesthesia. RESULTS: In 10- to 12-week-old rats, methoxamine (MX) produced vasoconstriction associated with an increase in [Ca2+ ]i and Ca2+ -sensitivity. In contrast, in 1-week-old rats these contractions were accompanied only by an increase in Ca2+ -sensitivity. All MX-induced effects were reduced by the Rho-kinase inhibitor Y-27632; this reduction was complete only in 1-week-old rats. The Rho-kinase specific site Thr855 on MYPT1 was increasingly phosphorylated by MX in vessels of 1-week-old, but not 10- to 12-week-old rats; this effect was also inhibited completely by Y-27632. The Rho-kinase inhibitor fasudil in a dose not affecting the pressor response to MX in 4- to 5-week-old rats reduced it considerably in 1-week-old rats. CONCLUSION: Our results suggest that the higher Ca2+ -sensitivity of arterial contraction in 1-week-old compared to 10- to 12-week-old rats is due to a greater Rho-kinase activity. Constitutively active Rho-kinase contributes to MX-induced contraction in 10- to 12-week-old rats. In 1-week-old rats, additional Rho-kinase activation is involved. This remodelling of the Rho-kinase pathway is associated with its increased contribution to adrenergic arterial pressure responses.
AIM: During early post-natal development, arterial contraction depends less on Ca2+ -signalling pathways but more on changes in Ca2+ -sensitivity compared to adult animals. Whether this difference is related to Rho-kinase, one of the major players affecting Ca2+ -sensitivity, is unknown for intact vessels. Thus, we tested the hypothesis that Rho-kinase critically contributes to the higher Ca2+ -sensitivity of contraction in intact arteries of 1-week-old rats. METHODS: We studied 1-week-old, 4- to 5-week-old and 10- to 12-week-old rats performing isometric myography, Ca2+ -fluorimetry and Western blotting using intact saphenous arteries and arterial pressure measurements under urethane anaesthesia. RESULTS: In 10- to 12-week-old rats, methoxamine (MX) produced vasoconstriction associated with an increase in [Ca2+ ]i and Ca2+ -sensitivity. In contrast, in 1-week-old rats these contractions were accompanied only by an increase in Ca2+ -sensitivity. All MX-induced effects were reduced by the Rho-kinase inhibitor Y-27632; this reduction was complete only in 1-week-old rats. The Rho-kinase specific site Thr855 on MYPT1 was increasingly phosphorylated by MX in vessels of 1-week-old, but not 10- to 12-week-old rats; this effect was also inhibited completely by Y-27632. The Rho-kinase inhibitor fasudil in a dose not affecting the pressor response to MX in 4- to 5-week-old rats reduced it considerably in 1-week-old rats. CONCLUSION: Our results suggest that the higher Ca2+ -sensitivity of arterial contraction in 1-week-old compared to 10- to 12-week-old rats is due to a greater Rho-kinase activity. Constitutively active Rho-kinase contributes to MX-induced contraction in 10- to 12-week-old rats. In 1-week-old rats, additional Rho-kinase activation is involved. This remodelling of the Rho-kinase pathway is associated with its increased contribution to adrenergic arterial pressure responses.
Authors: Dina K Gaynullina; Olga S Tarasova; Anastasia A Shvetsova; Anna A Borzykh; Rudolf Schubert Journal: Int J Mol Sci Date: 2022-05-26 Impact factor: 6.208
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