Physiology, Vasodilation

Issues of Concern

Although vasodilation is a natural response necessary for our bodies, in specific scenarios, excessive vasodilation can cause harm:

Anaphylaxis

Severe anaphylactic shock occurs when a rapid release of inflammatory mediators and cytokines triggers widespread vasodilation and increased vascular permeability. This situation leads to activating the inflammatory cascade, and immediate epinephrine is the first-line treatment.[1]

Septic Shock

Vasodilation is a normal response during inflammatory processes to increase blood flow to affected areas. However, in response to overwhelming infection, our bodies release numerous vasodilatory chemicals that cause inflammation and can lead to lethal hypotension.[2]

Cellular Level

Endothelial cells form the lining of blood vessels. These cells have the critical ability to rearrange and remodel the vasculature network. This feature of endothelial cells enables blood vessel changes and adequate blood flow to allow tissue growth and repair throughout the body. The endothelial cells are closest to the lumen of both arteries and veins. Surrounding the thin endothelial cell layer is a basal lamina, followed by varying amounts of smooth muscle cells and connective tissue dependent on the vessel’s function. In contrast to arteries and veins, capillaries are only a single layer of endothelial cells and pericytes.[3]

Development

Arteries and veins develop from initially small vessels composed of endothelial cells. The remaining components of the blood vessel lining are subsequently added upon signaling from the endothelial cells. Endothelial cells have mechanoreceptors that can sense stress. These allow the endothelial cells to signal the surrounding cells to produce connective tissue and smooth muscle adaptations to decrease stress and better accommodate the blood flow. If an area of the vascular system is damaged, the endothelial cells can undergo cell division and proliferate to repair areas. 

Angiogenesis is the process of new blood vessel formation. It occurs as a response to signaling from endothelial cells in an existing blood vessel. The most notable signals are vascular endothelial growth factor (VEGF) and fibroblast growth factor family (FGF).[4] 

Organ Systems Involved

Vasodilation affects all organ systems in the body. It increases blood flow to tissues throughout the body.

Function

Vasodilation increases blood flow to the body's tissues. In response to a need for oxygen or nutrients, tissues can release endogenous vasodilators. The result is a decrease in vascular resistance and an increase in capillary perfusion. A common example of this vasodilation response occurs during exercise. When exercising, the oxygen consumption by skeletal muscles rapidly increases, and it is necessary to increase the oxygen supply.

Mechanism

Vasodilation occurs when the smooth muscle located in the blood vessel walls relaxes. Relaxation can be due to either removing a contractile stimulus or inhibiting contractility. Numerous stimuli, including acetylcholine, ATP, adenosine, bradykinin, histamine, and shear stress, can activate eNOS and COX pathways that form nitric oxide (NO) and prostacyclin, respectively. Nitric oxide and prostacyclin produced within endothelial cells utilize intracellular secondary messengers. Nitric oxide primarily uses cyclic guanosine monophosphate (cGMP) for cellular effects, whereas prostacyclin effects are primarily mediated by cyclic adenosine monophosphate (cAMP).[5] These secondary messengers produced in the smooth muscle cells have downstream effects of causing a decrease in intracellular Ca and an increase in myosin light chain (MLC) phosphatase activity. In smooth muscle cells, active MLC phosphatase dephosphorylates the contracted actin and MLC complex, causing MLC to relax. Intracellular cations are removed by Ca and Mg-ATPases that sequester Ca back into the sarcoplasmic reticulum. Na/Ca antiporters in the plasma membrane can also decrease intracellular Ca. During relaxation, receptor-gated and voltage-gated Ca channels inhibit Ca entry into the smooth muscle cell.[6] The overall effect is the relaxation of the smooth muscle, which causes vasodilation. 

Other mediators involved in vasodilation are generated during enhanced muscle activity. These stimuli include pCO₂, lactate, K, and adenosine. Venous pCO₂ levels increase during exercise due to the high turnover of the Krebs cycle to meet the oxygen demands of skeletal muscle. A net gain in lactic acid is produced by exercising muscle due to increased glycolysis activity. Skeletal muscle cells release K ions into the interstitium during an action potential. During exercise, there is also an increase in the breakdown of adenosine triphosphate (ATP), yielding adenosine. The above mediators produced can diffuse to adjacent arterioles and have powerful vasodilatory effects, increasing the oxygen and nutrient supply to exercise muscle when demand is enhanced.[7]

Related Testing

Myocardial perfusion testing is a noninvasive diagnostic evaluation performed on suspected coronary artery disease patients. Pharmacological stimuli, most commonly adenosine, assess myocardial blood flow and coronary flow reserve. Adenosine is a powerful vasodilator used in these tests to produce maximal hyperemia during imaging.[8] Acute vasodilator testing can help to identify patients with pulmonary artery hypertension (PAH) who may respond to calcium channel blocker therapy. The testing procedure is performed during a right-heart catheterization. Vasodilatory medications are administered to assess the ability of the pulmonary arteries to relax before and after administration. Commonly used vasodilator drugs for the procedure include nitric oxide, epoprostenol, and adenosine.[9]

Pathophysiology

While multiple mechanisms can contribute to shock, 1 of the most common is distributive shock. Distributive shock characteristically demonstrates widespread peripheral vasodilation caused by vascular smooth muscle reactivity loss.[10] The vasodilation causes hypotension with resulting tissue hypoperfusion. Patients with septic shock, a type of distributive shock, often have elevated levels of catecholamines. The body releases the catecholamines as endogenous vasoconstrictors but cannot elicit an appropriate pressure response in the pathologic shock state. Additionally, endothelial cells can overexpress nitric oxide, contributing to even more pronounced vasodilation.[11] Management of this vasodilatory shock requires fluid resuscitation and the initiation of norepinephrine, a potent vasopressor. If this therapy is refractory, other vasopressors, such as vasopressin and epinephrine, can be added.[2]

Clinical Significance

Hypertension is the term for elevated blood pressure. More specifically, a systolic blood pressure ≥130 mmHg or a diastolic pressure ≥ 80 mmHg. Numerous medication classes are in clinical use to reduce high blood pressure by promoting vasodilation: 

• Calcium Channel Blockers: Block Ca²⁺ ions influx into vascular smooth muscle and cardiac muscle. The inhibition of Ca²⁺ leads to the relaxation of the vascular muscle cells and, therefore, vasodilation. These are primarily used to treat hypertension and angina.[12]
• Nitrates: Utilize secondary messengers that cause downstream effects of smooth muscle relaxation. Nitroglycerin is a nitrate most commonly used to relieve angina attacks.[13]
• Angiotensin-Converting Enzyme Inhibitors: Prevent the production of angiotensin II and inhibit the breakdown of bradykinin. Angiotensin II normally decreases NO production, and bradykinin stimulates NO release. The combined effects lead to increased NO, which causes vasodilation and can be used to lower blood pressure.[14]