Hypertension is linked to enhanced lymphatic contractile response via RGS16/RhoA/ROCK pathway

• Published in: American journal of physiology. Heart and circulatory physiology 2022-12, Vol.323 (6), p.H1118-H1129
• Main Authors: Mukohda, Masashi, Mizuno, Risuke, Saito, Fumiyo, Matsui, Toshiyasu, Ozaki, Hiroshi
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin II; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animal models; Animals; Antihypertensives; Blood Pressure; Blood vessels; Capillary pressure; Contractility; Ducts; Gene expression; Hydrochlorothiazide; Hypertension; Inhibitors; Lymph; Lymphatic Vessels - metabolism; Myosin; Phosphorylation; Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rho-associated kinase; rho-Associated Kinases; RhoA protein; Rocks; Rodents; Thoracic duct
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00496.2022

Lymph capillary network can be expected to alter blood pressure via regulating interstitial electrolyte and volume balance. However, the pathophysiology of lymphatic vessel in hypertension is poorly understood. In this study, we examined lymph vessel function focusing on contractile response in hypertensive rats. It was found that thoracic ducts isolated from adult (10-14 wk old) spontaneously hypertensive rats (SHRs) exhibited increased agonist-mediated contraction compared with age-matched Wistar-Kyoto (WKY) rats, whereas lymphatic contractions in younger (4 wk old) SHRs, exhibiting normal blood pressure, were no different compared with age-matched control rats. Tight regulation of blood pressure with antihypertensive drugs (hydrochlorothiazide/hydralazine) did not prevent the augmented lymphatic contraction in adult SHRs; however, treatment of SHRs with angiotensin II (ANG II) type 1 receptor blocker (losartan) for 6 wk abolished the augmentation of lymphatic contractions. In addition, ANG II infusion in Wistar rat caused augmented lymphatic contractile responses in the thoracic duct. The augmented contractions in adult SHRs were diminished by a ROCK inhibitor (Y-27632). Consistently, the thoracic ducts in SHRs showed significantly higher phosphorylation of myosin phosphatase targeting protein-1 than WKY rats. Furthermore, gene expression profiling of adult SHR lymphatics showed marked loss of regulator of G-protein signaling 16 (RGS16) mRNA, which was confirmed by the real-time PCR. Treatment with the RGS inhibitor CCG-63808 enhanced contractions in thoracic ducts from Wistar rats, which were abolished by the ROCK inhibitor. It is concluded that lymphatic contractile function was enhanced in hypertensive model rats, which could be mediated by dysregulation of the ROCK pathway possibly through RGS16. Lymph capillary controls interstitial electrolyte and volume balance, which may blunt increased blood pressure. However, the function of lymphatic vessel in hypertension is poorly understood. Our study showed that the lymphatic smooth muscle contractility is hyperreactive in two different hypertensive models. The lymphatic dysfunction could be mediated by dysregulation of ROCK pathway possibly through RGS16. The present finding supports a new concept showing the functional relationship between lymphatic contractile activity and hypertension.