Abstract 2: Compensatory Activation of the Sympathetic Nervous System after Deletion of Angiotensin Type 1 Receptors from Vascular Smooth Muscle Cells

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Abstract

Vasoconstriction is a signature physiological action of angiotensin II (Ang II). In order to define the physiological role of direct actions of AT1 receptors (AT1 R) in VSMCs, we generated mice with cell-specific deletion of AT1A R from VSMCs using a floxed Agtr1a allele and transgenic mouse lines expressing Cre only in VSMC lineages. We first compared systemic vascular responses to acute infusions of Ang II in mice lacking AT1A R in VSMCs (SMKOs) and controls. Surprisingly, brisk vasoconstrictor responses to 1μg/kg Ang II were preserved in SMKOs with peak increases in MAP only modestly reduced to ≈75% of control levels (15±2 vs. 23±1 mmHg P<0.05). Robust systemic vasoconstriction to Ang II was observed whether elimination of AT1A Rs was carried out in utero with a constitutively expressed SM-Cre or in adult animals with a tamoxifen-inducible SM-Cre. By contrast, Ang II-dependent vasoconstriction in the renal circulation was largely abrogated in SMKOs. Moreover, despite preserved systemic vascular responses to acute Ang II in SMKOs, their baseline BP was reduced and susceptibility to Ang II-dependent hypertension was significantly attenuated. To determine whether the minor AT1BR isoform might be responsible for their residual acute vascular responses, we generated SMKOs on an AT1B-null background (SMKO 1B-/-); the absence of AT1B Rs did not affect this response (SMKO 1B-/- 16±2 vs. SMKO-1B+/+ 15±2 mmHg; ns). As an alternative explanation, we tested for a possible involvement of the sympathetic nervous system (SNS) by infusing 400μg/kg of the α-adrenergic blocker phentolamine (PT) 5 min before giving Ang II. While PT had no effect on the intensity of Ang II-dependent vasoconstriction in controls (pre-PT: 23±1 vs. post-PT: 23±3 mm Hg), it almost completely abrogated vasoconstriction in SMKOs (pre-PT: 15±2 vs. post-PT: 3±1 mm Hg; P<0.005). Thus, we find a significant capacity for activation of the SNS to maintain acute Ang II-dependent vasoconstriction when AT1R signaling in VSMCs is absent. This pathway can induce brisk vasoconstriction in the systemic but not the renal circulation. Furthermore, despite compensatory activation of the SNS, deletion of AT1Rs from VSMCs reduces baseline BP and attenuates the severity of Ang II-dependent hypertension.

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