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

Abstract

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.

A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition

“…Although this report showed that PLK4 enhanced vimentin expression, there was no data on SMA transcription nor on SRF activity. In addition, a new report demonstrated that PLK1 positively regulated angiotensin-II activation of RhoA and actomyosin dynamics in murine vascular smooth muscle cells 13 . However, caution must be taken into the analogy of PLK4 with PLK1.…”

“…In this study, we primarily focused on the unique and under-studied family member PLK4 to investigate its role in FMT and the associated regulators. We also included PLK1, the representative of the PLK family 13 . We found that PLK4 inhibition constrained the rat aortic fibroblast proliferative/migratory behaviors, and somewhat to our surprise, also the nuclear activity of serum response factor, a transcription factor key to myofibroblastic transitions 2 .…”

Plk1 overexpression suppresses tumor development by inducing chromosomal instability

“…Plk1 belongs to a family of kinases with multiple roles in proliferative as well as postmitotic cells [10][11][12][13]23 . Among Polo-like kinases, Plk1 is considered an interesting target for cancer therapy due to the requirements for its kinase activity during cell division in tumor cells 13,17,21 .…”

“…In fact, treatment of Plk1-overexpressing cells with the Plk1 inhibitor BI2536 partially rescued these defects, suggesting that cytokinesis defects in Plk1-overexpressing cells are kinase-dependent and at least partially mediated by the Cep55-ESCRT pathway. Since Plk1 is also involved in cell migration and metastasis 49 , authophagy 50 , pentose phosphate metabolism 51 or blood pressure regulation 11 53,54 ), Aurora B (Ref. 8 ), Hec1 (Ref.…”

“…Plk1 is the most studied member of a conserved family of protein kinases (Plk1-5) involved in cell division as well as specific functions in postmitotic cells such as neurons 10 or smooth muscle cells 11 . Plk1 was originally identified in Drosophila as a protein involved in spindle formation and further studies have suggested critical functions for this kinase in centrosome biology, spindle dynamics, chromosome segregation and cytokinesis 12,13 .…”