Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis

• Published in: Nature medicine Vol. 23; no. 8; pp. 964 - 974
• Main Authors: de Cárcer, Guillermo, Wachowicz, Paulina, Martínez-Martínez, Sara, Oller, Jorge, Méndez-Barbero, Nerea, Escobar, Beatriz, González-Loyola, Alejandra, Takaki, Tohru, El Bakkali, Aicha, Cámara, Juan A, Jiménez-Borreguero, Luis J, Bustelo, Xosé R, Cañamero, Marta, Mulero, Francisca, de los Ángeles Sevilla, María, Montero, María Jose, Redondo, Juan Miguel, Malumbres, Marcos
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2017; Nature Publishing Group
• Subjects: 13/89; 14/19; 38/61; 42/41; 45/77; 631/80/128/1276; 631/80/128/1675; 631/80/304; 64/60; 692/699/75/593/1301; 96/31; 96/44; Actomyosin; Angiotensin; Angiotensin II; Angiotensin II - metabolism; Animals; Aorta - metabolism; Aorta - ultrastructure; Aortic Aneurysm - genetics; Aortic Aneurysm - metabolism; Aortic Rupture - genetics; Aortic Rupture - metabolism; Biomedicine; Blood Pressure; Blood vessels; Cancer; Cancer Research; Cancer therapies; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell division; Cell proliferation; Cell Proliferation - genetics; Contraction; Elasticity; Fitness; Fluorescent Antibody Technique; Gene Knockdown Techniques; Haploinsufficiency; Homeostasis; Homeostasis - genetics; Hypotension; Hypotension - genetics; Immunoblotting; Infectious Diseases; Metabolic Diseases; Mice; Microscopy, Electron, Transmission; Mitosis; Molecular Medicine; Muscle contraction; Muscle, Smooth, Vascular - metabolism; Muscles; Myocytes, Smooth Muscle - metabolism; Neurosciences; Physiological aspects; Physiological research; Polo-like kinase; Polo-Like Kinase 1; Protein kinases; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Real-Time Polymerase Chain Reaction; rho GTP-Binding Proteins - metabolism; rhoA GTP-Binding Protein; RhoA protein; Rupture; Rupturing; Skeletal muscle; Smooth muscle; Therapy; Vascular Stiffness - genetics; Spain
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4364

The kinase Plk1 has been studied primarily as a mitotic regulator in dividing cells, but de Cárcer et al . find that Plk1 deficiency or inhibition in mice causes nonmitotic defects in the vasculature, including aortic aneurysm and rupture, as well as defective vascular smooth muscle contractility. These results recommend a note of caution in the clinical use of PLK1 inhibitors as anticancer agents. Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo . Mechanistically, we found that Plk1 regulated angiotensin II–dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II–treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.