Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin–angiotensin–aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.

The vascular myogenic response refers to the acute reaction of a blood vessel to a change in transmural pressure. This response is critically important for the development of resting vascular tone, upon which other control mechanisms exert vasodilator and vasoconstrictor influences. The purpose of this review is to summarize and synthesize information regarding the cellular mechanism(s) underlying the myogenic response in blood vessels, with particular emphasis on arterioles. When necessary, experiments performed on larger blood vessels, visceral smooth muscle, and even striated muscle are cited. Mechanical aspects of myogenic behavior are discussed first, followed by electromechanical coupling mechanisms. Next, mechanotransduction by membrane-bound enzymes and involvement of second messengers, including calcium, are discussed. After this, the roles of the extracellular matrix, integrins, and the smooth muscle cytoskeleton are reviewed, with emphasis on short-term signaling mechanisms. Finally, suggestions are offered for possible future studies.

The mineralocorticoid receptor, targeted by drugs commonly used to treat hypertension, is generally thought to contribute to hypertension by altering kidney function. Using mice lacking the mineralocorticoid receptor specifically in smooth muscle cells, Iris Jaffe and her colleagues show that it also controls many aspects of vascular aging, including blood vessel tone, and that these vascular effects contribute to the mineralocorticoid receptor's prohypertensive actions. Hypertension is a cardiovascular risk factor present in over two-thirds of people over age 60 in North America; elevated blood pressure correlates with increased risk of heart attack, stroke and progression to heart and kidney failure. Current therapies are insufficient to control blood pressure in almost half of these patients1,2. The mineralocorticoid receptor (MR), acting in the kidney, is known to regulate blood pressure through aldosterone binding and stimulation of sodium retention3. However, recent studies support the concept that the MR also has extrarenal actions4,5,6,7 and that defects in sodium handling alone do not fully explain the development of hypertension and associated cardiovascular mortality8,9. We and others have identified functional MR in human vascular smooth muscle cells (SMCs)10,11, suggesting that vascular MR might directly regulate blood pressure. Here we show that mice with SMC-specific deficiency of the MR have decreased blood pressure as they age without defects in renal sodium handling or vascular structure. Aged mice lacking MR in SMCs (SMC-MR) have reduced vascular myogenic tone, agonist-dependent contraction and expression and activity of L-type calcium channels. Moreover, SMC-MR contributes to angiotensin II–induced vascular oxidative stress, vascular contraction and hypertension. This study identifies a new role for vascular MR in blood pressure control and in vascular aging and supports the emerging hypothesis that vascular tone contributes directly to systemic blood pressure.

Background: Patients with postural tachycardia syndrome ( POTS ) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS . We tested the hypothesis that they harbor functional autoantibodies to adrenergic receptors ( AR ). Methods and Results: Fourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR autoantibody‐mediated contractility using a perfused rat cremaster arteriole assay. A receptor‐transfected cell‐based assay was used to detect the presence of β1AR and β2AR autoantibodies. Data were normalized and expressed as a percentage of baseline. The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P <0.001) when coexisting β2AR dilative activity was blocked; and this was suppressed by α1AR blockade with prazosin. POTS sera acted as a partial α1AR antagonist significantly shifting phenylephrine contractility curves to the right. All POTS sera increased β1AR activation (130±3% of baseline, P <0.01) and a subset had increased β2AR activity versus healthy subjects. POTS sera shifted isoproterenol cAMP response curves to the left, consistent with enhanced β1AR and β2AR agonist activity. Autoantibody‐positive POTS sera demonstrated specific binding to β1AR, β2AR, and α1AR in transfected cells. Conclusions: POTS patients have elevated α1 AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1 AR for vasoconstriction and concurrent β AR ‐mediated tachycardia. Coexisting β1 AR and β2 AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.

The smooth muscle of arterioles responds to an increase in intraluminal pressure with vasoconstriction and with vasodilation when pressure is decreased. Such myogenic vasoconstriction provides a level of basal tone that enables arterioles to appropriately adjust diameter in response to neurohumoral stimuli. Key in this process of mechanotransduction is the role of changes in intracellular Ca²⁺. However, it is becoming clear that considerable complexity exists in the spatiotemporal characteristics of the Ca²⁺signal and that changes in intracellular Ca²⁺may play roles other than direct effects on the contractile process via activation of myosin light-chain phosphorylation. The involvement of Ca²⁺may extend to modulation of ion channels and release of Ca²⁺from the sarcoplasmic reticulum, alterations in Ca²⁺sensitivity, and coupling between cells within the vessel wall. The purpose of this brief review is to summarize the current literature relating to Ca²⁺and the arteriolar myogenic response. Consideration is given to coupling of Ca²⁺changes to the mechanical stimuli, sources of Ca²⁺, involvement of ion channels, and spatiotemporal aspects of intracellular Ca²⁺signaling.