title: Multimodal imaging in rats reveals impaired neurovascular coupling in sustained hypertension.
abstract: OBJECTIVE
  Arterial hypertension is an important risk factor for cerebrovascular diseases, such as transient ischemic attacks or stroke, and represents a major global health issue. The effects of hypertension on cerebral blood flow, particularly at the microvascular level, remain unknown.
  
  
  METHODS
  Using the spontaneously hypertensive rat (SHR) model, we examined cortical hemodynamic responses on whisker stimulation applying a multimodal imaging approach (multiwavelength spectroscopy, laser speckle imaging, and 2-photon microscopy). We assessed the effects of hypertension in 10-, 20-, and 40-week-old male SHRs and age-matched male Wistar Kyoto rats (CTRL) on hemodynamic responses, histology, and biochemical parameters. In 40-week-old animals, losartan or verapamil was administered for 10 weeks to test the reversibility of hypertension-induced impairments.
  
  
  RESULTS
  Increased arterial blood pressure was associated with a progressive impairment in functional hyperemia in 20- and 40-week-old SHRs; baseline capillary red blood cell velocity was increased in 40-week-old SHRs compared with age-matched CTRLs. Antihypertensive treatment reduced baseline capillary cerebral blood flow almost to CTRL values, whereas functional hyperemic signals did not improve after 10 weeks of drug therapy. Structural analyses of the microvascular network revealed no differences between normo- and hypertensive animals, whereas expression analyses of cerebral lysates showed signs of increased oxidative stress and signs of impaired endothelial homeostasis upon early hypertension.
  
  
  CONCLUSIONS
  Impaired neurovascular coupling in the SHR evolves upon sustained hypertension. Antihypertensive monotherapy using verapamil or losartan is not sufficient to abolish this functional impairment. These deficits in neurovascular coupling in response to sustained hypertension might contribute to accelerate progression of neurodegenerative diseases in chronic hypertension.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors.forename: Novella
authors.initials: N
authors.lastname: Calcinaghi
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Wyss
authors.forename: Renaud
authors.initials: R
authors.lastname: Jolivet
authors.forename: Anand
authors.initials: A
authors.lastname: Singh
authors.forename: Anna L
authors.initials: AL
authors.lastname: Keller
authors.forename: Stephan
authors.initials: S
authors.lastname: Winnik
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.forename: Alfred
authors.initials: A
authors.lastname: Buck
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.forename: Bruno
authors.initials: B
authors.lastname: Weber
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D036641:Microscopy, Fluorescence, Multiphoton; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013052:Spectrometry, X-Ray Emission; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D014700:Verapamil; D019808:Losartan
keywords: cerebrovascular circulation; hypertension; multimodality imaging; neurovascular coupling; spontaneously hypertensive rats