title: Intravital microscopy reveals endothelial dysfunction in resistance arterioles in Angiotensin II-induced hypertension.
abstract: It is known that hypertension is associated with endothelial dysfunction and that Angiotensin II (Ang II) is a key player in the pathogenesis of hypertension. We aimed to elucidate whether endothelial dysfunction is a specific feature of Ang II-mediated hypertension or a common finding of hypertension, independently of underlying etiology. We studied endothelial-dependent vasorelaxation in precapillary resistance arterioles and in various large-caliber conductance arteries in wild-type mice with Ang II-dependent hypertension (2-kidney 1-clip (2K1C) model) or Ang II-independent (volume overload) hypertension (1-kidney 1-clip model (1K1C)). Normotensive sham mice were used as controls. Aortic mechanical properties were also evaluated. Intravital microscopy of precapillary arterioles revealed a significantly impaired endothelium-dependent vasorelaxation in 2K1C mice compared with sham mice, as quantified by the ratio of acetylcholine (ACh)-induced over S-nitroso-N-acetyl-D,L-penicillamine (SNAP)-induced vasorelaxation (2K1C: 0.49±0.12 vs. sham: 0.87±0.11, P=0.018). In contrast, the ACh/SNAP ratio in volume-overload hypertension 1K1C mice was not significantly different from sham mice, indicating no specific endothelial dysfunction (1K1C: 0.77±0.27 vs. sham: 0.87±0.11, P=0.138). Mechanical aortic wall properties and endothelium-dependent vasorelaxation, assessed ex vivo in rings of large-caliber conductance (abdominal and thoracic aorta, carotid and femoral arteries), were not different between 2K1C, 1K1C and sham mice. Endothelial dysfunction is an early feature of Ang II- but not volume-overload-mediated hypertension. This occurs exclusively at the level of precapillary arterioles and not in conduit arteries. Our findings, if confirmed in clinical studies, will provide a better understanding of the pathophysiological mechanisms of hypertension.
authors.affiliation: Institute of Pathology, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schäfer
authors.forename: Maxime
authors.initials: M
authors.lastname: Pellegrin
authors.forename: Caroline
authors.initials: C
authors.lastname: Wyss
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Aubert
authors.forename: Jürg
authors.initials: J
authors.lastname: Nussberger
authors.forename: Daniel
authors.initials: D
authors.lastname: Hayoz
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Lucia
authors.initials: L
authors.lastname: Mazzolai
mesh_terms: D000109:Acetylcholine / Q000097:blood; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001158:Arteries / Q000503:physiopathology; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology*; D001696:Biomechanical Phenomena; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000503:physiopathology; D051379:Mice; D020030:Nitric Oxide Donors / Q000494:pharmacology; D012083:Renin / Q000097:blood; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D020030:Nitric Oxide Donors; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D026423:S-Nitroso-N-Acetylpenicillamine; D012083:Renin; D000109:Acetylcholine